Compounds and compositions for treating solid tumors by intratumoral administration

ABSTRACT

The invention provided herein includes pharmaceutical compositions comprising a TLR7 agonist having the structure of Formula (A), aluminum-containing particles, and one or more pharmaceutically acceptable excipient. The invention further provides the use of such compositions in the treatment of solid tumors either alone or in combination with one or more additional pharmaceutical compositions.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 17, 207, isnamed PAT057568-US-PSP_ST25.txt and is 73,200 bytes in size.

FIELD OF THE INVENTION

The invention provides methods of treating tumors by intratumoraladministration of TLR7 agonistst and the use of such agonists for thetreatment of tumors.

BACKGROUND OF THE INVENTION

Toll-like receptors (TLRs) are pattern recognition receptors which playan essential role in the innate immunity, by recognizing invasion ofmicrobial pathogens and initiating intracellular signal transductionpathways to trigger expression of genes, the products of which cancontrol innate immune responses. Specifically, Toll like receptor (TLR)agonists activate innate immune cells through the TLR-MyD88-NFkβ andIRF3/7 pathways. TLR7, TLR8, and TLR9 belong to a subfamily of TLRsbased on their genomic structure, sequence similarities, and homology.TLR7, TLR8, and TLR9 are located in intracellular endolysosomalcompartments and show a unique pattern of cell type-specific expressionthat is thought to be responsible for different pathogen responseprofiles.

Small molecule agonists of TLR7 and/or TLR8 have been reported and shownto activate innate immune responses by inducing selected cytokinebiosynthesis, the induction of co-stimulatory molecules, and byincreased antigen-presenting capacity. Such compounds includeimidazoquinoline amine derivatives (U.S. Pat. No. 4,689,338),imidazopyridine amine derivative (U.S. Pat. No. 5,446,153),imidazonaphthyridine derivative (U.S. Pat. No. 6,194,425),oxazoloquinoline amine derivatives (U.S. Pat. No. 6,110,929);thiazoloquinoline amine derivatives (U.S. Pat. No. 6,110,929),selenazoloquinoline amine derivatives (U.S. Pat. No. 6,110,929),pyrazolopyridine derivatives (U.S. Pat. No. 9,145,410), andbenzonaphthyridine amine derivatives (U.S. Pat. Nos. 8,466,167 and9,045,470).

The synthetic TLR7 agonist, Imiquimod(1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is FDA-approvedin a cream formulation for the topical treatment of cutaneous basal cellcarcinoma, actinic keratosis and genital warts, and has limited activityagainst cutaneous melanoma and breast tumors (J. Immunol. 2014, 193(9):4722-4731). Systemic administration of Imiquimod, and structurallysimilar Resiquimod, is limited by cytokine-mediated adverse effectsincluding severe flu-like symptoms (Expert Opin. Emerging Drugs (2010),15:544-555). Consequently, Imiquimod is used exclusively in topicalapplications and is not used to treat deep, non-cutaneous tumors such asmelanoma or solid tumors.

An injectable lipid modified imidazoquinoline (TLR7/8 dual agonist) thatforms a tissue depot with gradual, sustained release which allows forlocal TLR triggering activity without systemic cytokine release has beenreported (J. Immunol. 2014, 193(9): 4722-4731). However, this compoundwas shown to be ineffective for large tumors and in addition the serumconcentration of this compound 24 hours post subcutaneous administrationdecreased by approximately 50% (Journal for ImmunoTherapy of Cancer,2014, 2:12). Therefore, there remains a need for intratumoradministration of a TLR7 agonist with prolonged sustained release, whichmay benefit the treatment of large tumors.

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for solid tumorsand liquid tumors. The invention provides pharmaceutical compositionsand pharmaceutical combinations comprising a TLR7 agonist and asuspension of particles comprising aluminum. The invention also providespharmaceutical compositions and pharmaceutical combinations comprising aTLR7 agonist and a suspension of particles comprising aluminum for theuse in treating solid tumors or liquid tumors. The invention furtherprovides methods for treating a solid tumor or liquid tumor byadministrating to a subject in need thereof such pharmaceuticalcompositions or pharmaceutical combinations, and the use suchpharmaceutical compositions or pharmaceutical combinations in thetreatment of a solid tumor or a liquid tumor.

The present invention provides the following aspects, advantageousfeatures and specific embodiments, respectively alone or in combination,as listed in the following items:

The present invention provides the following aspects, advantageousfeatures and specific embodiments, respectively alone or in combination,as listed in the following items:

Item 1: A pharmaceutical composition comprising a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,aluminum-containing particles, a buffering agent, and one or morepharmaceutically acceptable excipients:

wherein:

-   -   R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or        —C(═O)CF₂P(O)(OH)₂;    -   R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴, —OL₂R⁴, —OR⁴,        —OL₂R⁶, —OL₂L₃R⁶, —OL₂L₃L₂R⁶, —OL₂L₃R₄—OL₂L₃L₂R⁴ or —OCH₃;    -   each R³ is independently selected from H and fluoro;    -   R⁴ is —P(O)(OH)₂,    -   R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   R⁶ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   L₁ is C₁-C₆alkylene, C₂-C₆alkenylene or        —((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene and        C₂-C₆alkenylene of L₁ are substituted with 0 to 4 fluoro groups;    -   each L₂ is independently selected from C₁-C₆alkylene and        —((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂        is substituted with 0 to 4 fluoro groups;    -   L₃ is arylene or a 5-6 membered heteroarylene;    -   each p is independently selected from 1, 2, 3, 4, 5 and 6, and    -   q is 1, 2, 3 or 4.

Item 2. The pharmaceutical composition of item 1, wherein thecomposition comprises a compound having the structure of Formula (A), ora pharmaceutically acceptable salt thereof, a buffering agent, apharmaceutically acceptable excipient selected from mannitol andsucrose, wherein the composition has a pH in the range of 6.5 to 9.0,and the aluminum-containing particles are a suspension ofaluminum-containing particles.

Item 3. The pharmaceutical composition of item 1 or item 2, wherein thecomposition comprises a compound having the structure of Formula (A), ora pharmaceutically acceptable salt thereof, a buffering agent, mannitol,wherein the composition has a pH in the range of 6.5 to 9.0, and thealuminum-containing particles are a suspension of aluminum-containingparticles.

Item 4. The pharmaceutical composition of any one of items 1 to 3,wherein the composition has a pH in the range of 7.0 to 8.0.

Item 5. The pharmaceutical composition of any one of items 1 to 4,wherein the composition has a pH in the range of 7.2 to 7.8.

Item 6. The pharmaceutical composition of any one of items 1 to 5,wherein the aluminum-containing particles are aluminum hydroxideparticles, aluminum oxyhydroxide particles or aluminum hydroxyphosphateparticles and the suspension of aluminum-containing particles is asuspension of aluminum hydroxide particles, aluminum oxyhydroxideparticles or aluminum hydroxyphosphate particles.

Item 7. The pharmaceutical composition of any one of items 1 to 6,wherein the aluminum-containing particles are aluminum hydroxideparticles, and the suspension of aluminum-containing particles is asuspension of aluminum hydroxide particles.

Item 8. The pharmaceutical composition of any one of items 1 to 7,wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum hydroxide particles, Tris buffer and mannitol.

Item 9. The pharmaceutical composition of any one of items 1 to 8,wherein the composition comprises 0.5 to 2 mg/mL of a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL.

Item 10. The pharmaceutical composition of any one of items 1 to 9,wherein the composition comprises 0.5 to 2 mg/mL of a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, 5-50 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL.

Item 11. The pharmaceutical composition of any one of items 1 to 10,wherein the composition comprises 0.5 to 2 mg/mL of a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL.

Item 12. The pharmaceutical composition of any one of items 1 to 11,wherein the composition comprises 1 mg/mL of a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, and whereinthe composition has a pH in the range of 7.0 to 8.0.

Item 13. The pharmaceutical composition of any one of items 1 to 12,wherein the composition comprises 1 mg/mL of a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, and whereinthe composition has a pH in the range of 7.0 to 8.0.

Item 14. The pharmaceutical composition of any one of items 1 to 12,wherein the composition comprises 1 mg/mL of a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, and whereinthe composition has a pH of in the range of 7.0 to 8.0.

Item 15. The pharmaceutical composition of any one of items 1 to 12,wherein the composition comprises 1 mg/mL of a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 5.5% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, and whereinthe composition has a pH of in the range of 7.0 to 8.0.

Item 16. The pharmaceutical composition of any one of items 1 to 7,wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum hydroxide particles, Tris buffer and sucrose.

Item 17. The pharmaceutical composition of any one of items 1 to 7 or16, wherein the composition comprises 0.5 to 2 mg/mL of a compoundhaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, 5-100 mM Tris buffer, 5-10% (w/v) sucrose, and asuspension of aluminum hydroxide particles having an aluminum content of1 to 4 mg/mL.

Item 18. The pharmaceutical composition of any one of items 1 to 7 or 16to 17, wherein the composition comprises 0.5 to 2 mg/mL of a compoundhaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, 5-50 mM Tris buffer, 5-10% (w/v) sucrose, and a suspensionof aluminum hydroxide particles having an aluminum content of 1 to 4mg/mL.

Item 19. The pharmaceutical composition of any one of items 1 to 7 or 15to 17, wherein the composition comprises 0.5 to 2 mg/mL of a compoundhaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose, and a suspensionof aluminum hydroxide particles having an aluminum content of 1 to 4mg/mL.

Item 20. The pharmaceutical composition of any one of items 1 to 7 or 16to 20, wherein the composition comprises 1 mg/mL of a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose, and a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, andwherein the composition has a pH in the range of 7.0 to 8.0.

Item 21. The pharmaceutical composition of any one of items 1 to 7 or 16to 20, wherein the composition comprises 1 mg/mL of a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, 16 mM Tris buffer, 7.5% (w/v) sucrose, and a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, andwherein the composition has a pH in the range of 7.0 to 8.0.

Item 22. The pharmaceutical composition of any one of items 1 to 7 or 16to 21, wherein the composition comprises 1 mg/mL of a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, 5 mM Tris buffer, 8.25% (w/v) sucrose, and a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, andwherein the composition has a pH in the range of 7.0 to 8.0.

Item 23. The pharmaceutical composition of any one of items 1 to 22,wherein the (w/w) ratio of the weight of compound of Formula A to theweight of aluminum in the suspension of aluminum-containing particles isin the range from 1:1 to 1:20.

Item 24. The pharmaceutical composition of any one of items 1 to 23,wherein the (w/w) ratio of the weight of compound of Formula A to theweight of aluminum in the suspension of aluminum-containing particles isin the range from 1:1.5 to 1:2.5.

Item 25. The pharmaceutical composition of any one of items 1 to 22,wherein the (w/w) ratio of the weight of compound of Formula A to theweight of aluminum in the suspension of aluminum-containing particles is1:1.5.

Item 26. The pharmaceutical composition of any one of items 1 to 22,wherein the (w/w) ratio of the weight of compound of Formula A to theweight of aluminum in the suspension of aluminum-containing particles is1:2.

Item 27. The pharmaceutical composition of any one of items 1 to 15 or23, wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of compound ofFormula A to the weight of aluminum in the suspension of particles is1:20.

Item 28. The pharmaceutical composition of any one of items 1 to 15 or23, wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of compound ofFormula A to the weight of aluminum in the suspension of particles is1:2 and the composition has a pH in the range of 7.0 to 8.0.

Item 29. The pharmaceutical composition of any one of items 1 to 15 or23, wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 16 mM Trisbuffer, 7.5 (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of compound ofFormula A to the weight of aluminum in the suspension of particles is1:2 and the composition has a pH of in the range of 7.0 to 8.0.

Item 30. The pharmaceutical composition of any one of items 1 to 15 or23, wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5 mM Trisbuffer, 8.25 (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of compound ofFormula A to the weight of aluminum in the suspension of particles is1:2 and the composition has a pH of in the range of 7.0 to 8.0.

Item 31. The pharmaceutical composition of any one of items 1 to 15 or23, wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5 mM Trisbuffer, 5.5 (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of compound ofFormula A to the weight of aluminum in the suspension of particles is1:2 and the composition has a pH of in the range of 7.0 to 8.0.

Item 32. The pharmaceutical composition of any one of items 16 to 23,wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the compound of Formula A tothe aluminum in the suspension of particles is 1:20.

Item 33. The pharmaceutical composition of any one of items 16 to 23,wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the compound of Formula A tothe aluminum in the suspension of particles is 1:2 and the compositionhas a pH in the range of 7.0 to 8.0.

Item 34. The pharmaceutical composition of any one of items 16 to 23,wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 16 mM Trisbuffer, 7.5 (w/v) sucrose, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the compound of Formula A tothe aluminum in the suspension of particles is 1:2 and the compositionhas a pH in the range of 7.0 to 8.0.

Item 35. The pharmaceutical composition of any one of items 16 to 23,wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5 mM Trisbuffer, 8.25 (w/v) sucrose, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the compound of Formula A tothe aluminum in the suspension of particles is 1:2 and the compositionhas a pH in the range of 7.0 to 8.0.

Item 36. The pharmaceutical composition of any one of items 1 to 34,wherein the compound having the structure of Formula (A) is:

-   3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid;-   3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid;-   3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid;-   3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid;-   3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid;-   3-(5-amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid, and-   3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic    acid.-   (3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonic    acid;-   4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl    dihydrogen phosphate;-   ((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonic    acid;-   5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonic    acid;-   (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonic    acid;-   (3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropyl)phosphonic    acid;-   3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonic    acid;-   2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonic    acid;-   (3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonic    acid;-   (2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonic    acid;-   (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonic    acid;-   (6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonic    acid;-   (4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonic    acid;-   (2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl)phosphonic    acid;-   (5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonic    acid, and-   (4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonic    acid.-   2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonic    acid;-   (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonic    acid;-   2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonic    acid;-   (E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonic    acid, or-   (5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonic    acid.

Item 37. The pharmaceutical composition of any one of items 1 to 36,wherein the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Item 38. The pharmaceutical composition of any one of items 1 to 36,wherein the compound is3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Item 39. The pharmaceutical composition of any one of items 1 to 8,wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles, Tris buffer and mannitol.

Item 40. The pharmaceutical composition of any one of items 1 to 8 or39, wherein the composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.

Item 41. The pharmaceutical composition of any one of items 1 to 8 or 39to 40, wherein the composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-50 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.

Item 42. The pharmaceutical composition of any one of items 1 to 8 or 39to 41, wherein the composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.

Item 43. The pharmaceutical composition of any one of items 1 to 8 or 39to 42, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, and wherein thecomposition has a pH in the range of 7.0 to 8.0.

Item 44. The pharmaceutical composition of any one of items 1 to 8 or 39to 43, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.

Item 45. The pharmaceutical composition of any one of items 1 to 8 or 39to 43, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.

Item 46. The pharmaceutical composition of any one of items 1 to 8 or 39to 43, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,5.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.

Item 47. The pharmaceutical composition of any one of items 1 to 7,wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles, Tris buffer and sucrose.

Item 48. The pharmaceutical composition of any one of items 1 to 7 or47, wherein the composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.

Item 49. The pharmaceutical composition of any one of items 1 to 7 or 47to 48, wherein the composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-50 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.

Item 50. The pharmaceutical composition of any one of items 1 to 7 or 47to 49, wherein the composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.

Item 51. The pharmaceutical composition of any one of items 1 to 7 or 47to 50, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, and wherein thecomposition has a pH in the range of 7.0 to 8.0.

Item 52. The pharmaceutical composition of any one of items 1 to 7 or 47to 51, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.

Item 53. The pharmaceutical composition of any one of items 1 to 7 or 47to 52, wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.

Item 54. The pharmaceutical composition of any one of claims 1 to 8 or39 to 53, wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, to the weight ofaluminum in the suspension of aluminum-containing particles is in therange from 1:1 to 1:20.

Item 55. The pharmaceutical composition of any one of claims 1 to 8 or39 to 53, wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, to the weight ofaluminum in the suspension of aluminum-containing particles is in therange from 1:1.5 to 1:2.5.

Item 56. The pharmaceutical composition of any one of claims 1 to 8 or39 to 53, wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, to the weight ofaluminum in the suspension of aluminum-containing particles is 1:1.5.

Item 57. The pharmaceutical composition of any one of claims 1 to 8 or39 to 53, wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, to the weight ofaluminum in the suspension of aluminum-containing particles is 1:2.

Item 58. The pharmaceutical composition of any one of items 1 to 8 or 39to 45, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:20.

Item 59. The pharmaceutical composition of any one of items 1 to 8 or 39to 45, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 60. The pharmaceutical composition of any one of items 1 to 8 or 39to 45, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5 (w/v) mannitol, and a suspension of aluminum hydroxide particles,and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 61. The pharmaceutical composition of any one of items 1 to 8 or 39to 45, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25 (w/v) mannitol, and a suspension of aluminum hydroxide particles,and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 62. The pharmaceutical composition of any one of items 1 to 8 or 39to 45, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,5.5 (w/v) mannitol, and a suspension of aluminum hydroxide particles,and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 63. The pharmaceutical composition of any one of items 1 to 7 or 47to 53, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:20.

Item 64. The pharmaceutical composition of any one of items 1 to 7 or 47to 53, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 65. The pharmaceutical composition of any one of items 1 to 7 or 47to 53, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5 (w/v) sucrose, and a suspension of aluminum hydroxide particles, andwherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 66. The pharmaceutical composition of any one of items 1 to 7 or 47to 53, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25 (w/v) sucrose, and a suspension of aluminum hydroxide particles,and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:2 andthe composition has a pH in the range of 7.0 to 8.0.

Item 67. The pharmaceutical composition of any one of items 1 to 66further comprising an additional therapeutic agent.

Item 68. The pharmaceutical composition of item 67, wherein theadditional therapeutic agents is a checkpoint inhibitor, a TLR9 agonist,a TLR8 agonist, a TLR7 agonist, a STING agonist or a chemotherapeuticagent.

Item 69. A pharmaceutical combination comprising a first pharmaceuticalcomposition of any one of items 1 to 66, and a second pharmaceuticalcomposition comprising a checkpoint inhibitor, a TLR9 agonist, a TLR8agonist, a TLR7 agonist, a STING agonist or a chemotherapeutic agent.

Item 70. A pharmaceutical combination comprising a first pharmaceuticalcomposition of any one of items 1 to 66, a second pharmaceuticalcomposition comprising a checkpoint inhibitor, a TLR9 agonist, a TLR8agonist, a TLR7 agonist, a STING agonist or a chemotherapeutic agent anda third pharmaceutical composition comprising a checkpoint inhibitor, aTLR9 agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist or achemotherapeutic agent

Item 71. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66, and    -   b) a second pharmaceutical composition comprising a checkpoint        inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1        receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor        inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor,        a PD-L1 inhibitor or a PD-L2 inhibitor.

Item 72. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66, and    -   b) a second pharmaceutical composition comprising a PD-1        receptor inhibitor.

Item 73. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66, and    -   b) a second pharmaceutical composition comprising a PD-L1        inhibitor.

Item 74. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody.

Item 75. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody.

Item 76. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66,    -   b) a second pharmaceutical composition comprising a checkpoint        inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1        receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor        inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor,        a PD-L1 inhibitor or a PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising a checkpoint        inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1        receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor        inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor,        a PD-L1 inhibitor or a PD-L2 inhibitor,    -   wherein the checkpoint of the third composition is different        than the checkpoint inhibitor in the second composition.

Item 77. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66,    -   b) a second pharmaceutical composition comprising a PD-L1        inhibitor, and    -   c) a third pharmaceutical composition comprising a CTLA-4        receptor inhibitor.

Item 78. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66,    -   b) a second pharmaceutical composition comprising a PD-1        inhibitor, and    -   c) a third pharmaceutical composition comprising a CTLA-4        receptor inhibitor.

Item 79. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody.

Item 80. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody.

Item 81. A method for treating a solid tumor by administering to asubject in need thereof a pharmaceutical composition of any one of items1 to 68, or a pharmaceutical combination of any one of items 69 to 80.

Item 82. A method for treating a solid tumor by administering to asubject in need thereof a pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66,    -   b) a second pharmaceutical composition comprising a checkpoint        inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1        receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor        inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor,        a PD-L1 inhibitor or a PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising a checkpoint        inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1        receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor        inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor,        a PD-L1 inhibitor or a PD-L2 inhibitor,    -   wherein the checkpoint of the third composition is different        than the checkpoint inhibitor in the second composition, and    -   wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion.

Item 83. A method for treating a solid tumor by administering to asubject in need thereof a pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition of any one of items 1 to        66, and a    -   b) a second pharmaceutical composition comprising a checkpoint        inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1        receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor        inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor,        a PD-L1 inhibitor or a PD-L2 inhibitor,    -   wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Item 84. The method of any one of items 81 to 33, wherein the solidtumor is head and neck squamous cell carcinoma (HNSCC), melanoma or avisceral tumor.

Item 85. Use of a pharmaceutical composition of any one of items 1 to68, or use a pharmaceutical combination of any one of items 69 to 80, intreating a solid tumor.

Item 86. The use of item 85, wherein the solid tumor is head and necksquamous cell carcinoma (HNSCC), melanoma or a visceral tumor.

Item 87. A pharmaceutical composition of any one of items 1 to 68, or apharmaceutical combination of any one of items 69 to 80, for use intreating a solid tumor.

Item 88. The pharmaceutical composition of item 87, wherein the solidtumor is head and neck squamous cell carcinoma (HNSCC), melanoma or avisceral tumor.

Item 89. A lyophilisate comprising a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable excipients:

wherein:

-   -   R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or        —C(═O)CF₂P(O)(OH)₂;    -   R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴, —OL₂R⁴, —OR⁴,        —OL₂R⁶, —OL₂L₃R⁶, -OL₂L₃L₂R⁶, —OL₂L₃R₄—OL₂L₃L₂R⁴ or —OCH₃;    -   each R³ is independently selected from H and fluoro;    -   R⁴ is —P(O)(OH)₂,    -   R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   R⁶ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   L₁ is C₁-C₆alkylene, C₂-C₆alkenylene or        —((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene and        C₂-C₆alkenylene of L₁ are substituted with 0 to 4 fluoro groups;    -   each L₂ is independently selected from C₁-C₆alkylene and        —((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂        is substituted with 0 to 4 fluoro groups;    -   L₃ is arylene or a 5-6 membered heteroarylene;    -   each p is independently selected from 1, 2, 3, 4, 5 and 6, and    -   q is 1, 2, 3 or 4.

Item 90. The lyophilisate of item 89, wherein the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Item 91. A lyophilisate prepared from a solution having a pH between 6.5and 9.0 and comprising a a compound having the structure of Formula (A),or a pharmaceutically acceptable salt thereof, and a buffering agent:

wherein:

-   -   R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or        —C(═O)CF₂P(O)(OH)₂;    -   R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴, —OL₂R⁴, —OR⁴,        —OL₂R⁶, —OL₂L₃R⁶, —OL₂L₃L₂R⁶, —OL₂L₃R₄—OL₂L₃L₂R⁴ or —OCH₃;    -   each R³ is independently selected from H and fluoro;    -   R⁴ is —P(O)(OH)₂,    -   R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   R⁶ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   L₁ is C₁-C₆alkylene, C₂-C₆alkenylene or        —((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene and        C₂-C₆alkenylene of L₁ are substituted with 0 to 4 fluoro groups;    -   each L₂ is independently selected from C₁-C₆alkylene and        —((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂        is substituted with 0 to 4 fluoro groups;    -   L₃ is arylene or a 5-6 membered heteroarylene;    -   each p is independently selected from 1, 2, 3, 4, 5 and 6, and    -   q is 1, 2, 3 or 4.

Item 92. The lyophilisate of Item 91, wherein the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Item 93. A pharmaceutical composition prepared by reconstituting alyophilisate of any one of items 89 to 92 with water and admixing with asuspension of aluminum-containing particles.

Item 94. The pharmaceutical composition of item 93 prepared byreconstituting a lyophilisate of any one of items 89 to 92 with waterand admixing with a suspension of aluminum-containing particles havingan aluminum content of 1 to 4 mg/mL.

Item 95. The pharmaceutical composition of items 93 to 94, wherein thealuminum-containing particles are aluminum hydroxide particles.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 : Plasma concentration-time profiles of Compound 15 in a MC38tumor bearing C57/BL6 mice following a single intratumoral (i.t.) orsubcutaneous (sc) injection of 100 μg free Compound 15 solution orCompound 15 adsorbed to aluminum hydroxide at 1:1.5, w/w ratio.

FIG. 2 : A) Plasma TNFα levels in a MC38 tumor bearing C57/BL6 micefollowing a single intratumoral (i.t.) or subcutaneous (sc) injection ofCompound 15 adsorbed to aluminum hydroxide at 1:1.5, w/w ratio.

-   -   B) Plasma IL-6 levels from a MC38 tumor bearing C57/BL6 mice        following a single intratumoral (i.t.) or subcutaneous (sc)        injection of Compound 15 adsorbed to aluminum hydroxide at        1:1.5, w/w ratio.    -   C) Plasma IP-10 levels from a MC38 tumor bearing C57/BL6 mice        following a single intratumoral (i.t.) or subcutaneous (sc)        injection of Compound 15 adsorbed to aluminum hydroxide at        1:1.5, w/w ratio.

FIG. 3 : A) Plasma TNFα levels in a MC38 tumor bearing C57/BL6 micefollowing a single intratumoral (i.t.) or subcutaneous (sc) injection ofCompound 15 adsorbed to aluminum hydroxide at 1:2, w/w ratio.

-   -   B) Plasma IL-6 levels in a MC38 tumor bearing C57/BL6 mice        following a single intratumoral (i.t.) or subcutaneous (sc)        injection of Compound 15 adsorbed to aluminum hydroxide at 1:2,        w/w ratio.    -   C) Plasma IP-10 levels in a MC38 tumor bearing C57/BL6 mice        following a single intratumoral (i.t.) or subcutaneous (sc)        injection of Compound 15 adsorbed to aluminum hydroxide at 1:2,        w/w ratio.

FIG. 4 : Plasma concentration-time profiles of Compound 15 in maleWistar rats following a single subcutaneous (sc) injection of 600 μgfree Compound 15 in 100 mM Tris buffer (pH 7.4), a single subcutaneous(sc) injection of 600 μg free Compound 15 adsorbed to aluminum hydroxidein 100 mM Tris buffer (pH 7.4) at 1:2.5, w/w ratio, (97% bound), asingle subcutaneous (sc) injection of 200 μg free Compound 15 adsorbedto aluminum hydroxide in 100 mM Tris buffer (pH 7.4) at 1:2.5, w/wratio, (94% bound) and a single subcutaneous (sc) injection of 50 μgfree Compound 15 in 100 mM Tris buffer (pH 7.4) adsorbed to aluminumhydroxide at 1:2.5, w/w ratio, (91% bound).

FIG. 5 : A) Plasma concentration-time profiles of Compound 15 in maleWistar rats following a single subcutaneous injection for 600 μg ofCompound 15 in 100 mM Tris buffer (pH 7.4), a single subcutaneousinjection of 600 μg of Compound 15 adsorbed to aluminum hydroxide in 100mM Tris buffer buffer (pH 7.4) at 1:1.7, w/w ratio, (98% bound) and asingle subcutaneous injection of 50 μg of Compound 15 adsorbed toaluminum hydroxide in 100 mM Tris buffer buffer (pH 7.4) at 1:20, w/wratio, (98% bound)

-   -   B) Plasma IP-10 levels in male Wistar rats following a single        subcutaneous injection for 600 μg of Compound 15 in 100 mM Tris        buffer (pH 7.4), a single subcutaneous injection of 600 μg of        Compound 15 adsorbed to aluminum hydroxide in 100 mM Tris buffer        buffer (pH 7.4) at 1:1.7, w/w ratio, (98% bound) and a single        subcutaneous injection of 50 μg of Compound 15 adsorbed to        aluminum hydroxide in 100 mM Tris buffer buffer (pH 7.4) at        1:20, w/w ratio, (98% bound).

FIG. 6 : Serum aluminum concentrations vs time post dose of aluminumhydroxide alone (Group 2) or post dose of Compound 15 with aluminumhydroxide (Group 5).

FIG. 7 : Aluminum serum concentration vs. time profile aftersubcutaneous administration of Compound 15 adsorbed to aluminumhydroxide and intravenous administration of AlCl₃·6H₂O in saline.

FIG. 8 : Efficacy and dose response in A20 mouse lymphoma modelfollowing 2 weekly intra tumoral (i.t.) injections of different doses ofCompound 15/aluminum hydroxide (at fixed ratio of 1:1.5, w/w, and 97%bound).

FIG. 9 . Efficacy following a single 100 μg i.t. injection in A20 mouselymphoma model of Compound 15/aluminum hydroxide at Compound 15 toaluminum hydroxide w/w ratios of 1:1.5, 1:1 and 1:0.5.

FIG. 10 : A) Efficacy at the intratumor injection site followingadministration of Compound 15/aluminum hydroxide, an anti-PDL1 antibodyor an anti-CTLA4 antibody as single agents or after the administrationof combinations of Compound 15/aluminum hydroxide and an anti-PDL1antibody and/or an anti-CTLA4 antibody. Significant differences werecalculated using One-Way ANOVA post hoc Tukey multiple comparison teston post implant day 22 with N=9 per group, In treated site tumor AntiPD-L1 alone was significantly different, (*p<0.05). Compound 15/aluminumhydroxide, Compound 15/aluminum hydroxide with anti PD-L1 or antiCTLA4,Compound 15/aluminum hydroxide with anti PD-L1 and antiCTLA4 weresignificant different (**** p<0.0001).

-   -   B) Efficacy at a site distant from the injection site following        administration of Compound 15/aluminum hydroxide, an anti-PDL1        antibody or an anti-CTLA4 antibody as single agents or after the        administration of combinations of Compound 15/aluminum hydroxide        and an anti-PDL1 antibody and/or an anti-CTLA4 antibody.        Significant differences were calculated using One-Way ANOVA post        hoc Tukey multiple comparison test on post implant day 19 with        N=9 per group, in distant site tumor, anti CTLA4 alone was not        significantly different from no treatment, (*p>0.05). Anti PD-L1        alone was significantly different, (p<0.001). Compound        15/aluminum hydroxide alone was significantly different,        (**p<0.01). Compound 15/aluminum hydroxide with anti PD-L1 was        significantly different, (****p<0.0001). Compound 15/aluminum        hydroxide with anti CTLA4 was significantly different,        (*p<0.05). Compound 15/aluminum hydroxide with anti PD-L1 and        antiCTLA4 was significantly different, (****p<0.0001).    -   C) Efficacy at the intratumor injection site following        administration of Compound 15 or Compound 15/aluminum hydroxide        as single agents, or after the administration of the combination        of an anti-PDL1 antibody and an anti-CTLA4 antibody or after the        administration of the triple combinations of Compound 15 and an        anti-PDL1 antibody and an anti-CTLA4 antibody or after        administration of the triple combinations of Compound        15/aluminum hydroxide and an anti-PDL1 antibody and an        anti-CTLA4 antibody.    -   D) Efficacy at a site distant from the injection site following        administration of Compound or Compound 15/aluminum hydroxide as        single agents, or after the administration of the combination of        an anti-PDL1 antibody and an anti-CTLA4 antibody or after the        administration of the triple combinations of Compound 15 and an        anti-PDL1 antibody and an anti-CTLA4 antibody or after        administration of the triple combinations of Compound        15/aluminum hydroxide and an anti-PDL1 antibody and an        anti-CTLA4 antibody.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “alkenyl” or “alkene,” as used herein, refers to a partiallyunsaturated branched or straight chain hydrocarbon having at least onecarbon-carbon double bond. Atoms oriented about the double bond are ineither the cis (Z) or trans (E) conformation. In certain embodiments,such alkenyl or alkene group are optionally substituted. The terms“C₂-C₃alkenyl”, “C₂-C₄alkenyl”, “C₂-C₆alkenyl”, “C₂-C₆alkenyl”,“C₂-C₇alkenyl”, and “C₂-C₈alkenyl” refer to an alkenyl group containingat least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atoms, respectively.In preferred embodiments, an alkenyl group generally is a C₂-C₆ alkenyl.Non-limiting examples of alkenyl groups include ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and thelike.

The term “alkenylene,” as used herein, refers to a partially unsaturatedbranched or straight chain divalent hydrocarbon radical derived from analkenyl group. In certain embodiments, such alkenylene group areoptionally substituted. As used herein, the term “C₂-C₃alkenylene”,“C₂-C₄alkenylene”, “C₂-C₅alkenylene”, “C₂-C₆alkenylene”,“C₂-C₇alkenylene”, and “C₂-C₈alkenylene” refer to an alkenylene groupcontaining at least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atomsrespectively. In preferred embodiments, an alkenylene group generally isa C₂-C₆ alkenylene. Non-limiting examples of alkenylene groups as usedherein include, ethenylene, propenylene, butenylene, pentenylene,hexenylene, heptenylene, octenylene, nonenylene, decenylene and thelike.

The term “alkyl,” as used herein, refers to a saturated branched orstraight chain hydrocarbon. The terms “C₁-C₃alkyl”, “C₁-C₄alkyl”,“C₁-C₆alkyl”, “C₁-C₆alkyl”, “C₁-C₇alkyl” and “C₁-C₆alkyl” refer to analkyl group containing at least 1, and at most 3, 4, 5, 6, 7 or 8 carbonatoms, respectively. In preferred embodiments, an alkyl group generallyis a C₁-C₆ alkyl. Non-limiting examples of alkyl groups as used hereininclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl,decyl and the like.

The term “alkylene,” as used herein, refers to a saturated branched orstraight chain divalent hydrocarbon radical derived from an alkyl group.In certain embodiments such alkylene groups are optionally substituted.As used herein, the terms “C₁-C₃alkylene”, “C₁-C₄alkylene”,“C₁-C₆alkylene”, “C₁-C₆alkylene”, “C₁-C₇alkylene” and “C₁-C₆alkylene”refer to an alkylene group containing at least 1, and at most 3, 4, 5,6, 7 or 8 carbon atoms respectively. In preferred embodiments, analkylene group generally is a C₁-C₆alkylene. Non-limiting examples ofalkylene groups as used herein include, methylene, ethylene,n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene,t-butylene, n-pentylene, isopentylene, hexylene and the like.

The term “aryl,” as used herein, refers to phenyl or naphthalene.

The term “arylene,” as used herein means a divalent radical derived froman aryl group. In preferred embodiments, an arylene group is aphenylene.

The term “5-6 membered heteroaryl,” as used herein, refers to amonocyclic aromatic ring structure having 5 or 6 ring members, wherein 1to 3 ring members are independently selected from the heteroatoms N, Oand S. Non-limiting examples of 5-6 membered heteroaryls include 2- or3-furyl; 2- or 3-thienyl; 1-, 2- or 3-pyrrolyl; 2-, 4-, or 5-oxazolyl;2-, 4-, or 5-thiazolyl; 1-, 2-, 4-, or 5-imidazolyl; 1-, 3-, 4-, or5-pyrazolyl; 3-, 4-, or 5-isoxazolyl; 3-, 4-, or 5-isothiazolyl; 4- or5-1,2,3-oxadiazolyl; 4- or 5-1,2,3-triazolyl; 2- or5-1,3,4-thiadiazolyl; 2-, 3-, or 4-pyridyl; 3-, 4-, 5- or 6-pyridazinyl;2-, 4-, 5- or 6-pyrimidinyl, and 2- or 3-pyrazinyl.

The term “heteroatoms” as used herein, refers to nitrogen (N), oxygen(O) or sulfur (S) atoms.

The term “5-6 membered heteroarylene,” as used herein, means a divalentradical derived from a 5-6 membered heteroaryl group.

The term “liquid tumor,” as used herein, refers to cancers which affectbone marrow, blood cells and the lymphatic system. An example of aliquid tumor is leukemia.

The term “solid tumor,” as used herein, refers to an abnormal mass oftissue that usually does not contain cysts or liquid areas. In general,the term refers to cancerous (malignant) tumors, although a solid tumormay be a non-cancerous (benign) tumor. Examples of solid tumors aresarcomas, carcinomas, and lymphomas, which include, but are not limitedto, a breast cancer tumor, a bladder cancer tumor, a head and neckcancer tumor (e.g. head and neck squamous cell carcinoma (HNSCC)), anon-small cell lung cancer tumor, a small cell lung cancer tumor, acolorectal cancer tumor, a gastrointestinal stromal tumor, agastroesophageal carcinoma, a renal cell cancer tumor, a prostate cancertumor, a liver cancer tumor, a colon cancer tumor, a pancreatic cancertumor, an ovarian cancer tumor, a lymphoma, a cutaneous T-cell lymphoma,visceral tumors or a melanoma.

The terms “combination” or “pharmaceutical combination,” as used hereinmean a product that results from the mixing or combining of more thanone active ingredient and includes both fixed and non-fixed combinationsof the active ingredients. The term “fixed combination” means that theactive ingredients, by way of example, a compound disclosed herein andone or more additional therapeutic agent are administered to a subjectsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, by way ofexample, a compound disclosed herein and one or more additionaltherapeutic agent, are administered to a subject as separate entitieseither simultaneously, concurrently or sequentially with no specifictime limits, wherein such administration provides therapeuticallyeffective levels of the active ingredients in the body of the subject.The latter also applies to cocktail therapy, e.g. the administration of3 or more active ingredients.

The terms “composition” or “pharmaceutical composition,” as used herein,refers to a mixture of a compound disclosed herein with at least one andoptionally more than one other pharmaceutically acceptable chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients.

The term “an optical isomer” or “a stereoisomer”, as used herein, refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. The term “chiral” refers to molecules whichhave the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner. Therefore, the inventionincludes enantiomers, diastereomers or racemates of the compound.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term is used to designate a racemic mixture whereappropriate. “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain compounds described herein contain one ormore asymmetric centers or axes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-.

The term “pharmaceutically acceptable salt,” as used herein, refers to asalt which does not abrogate the biological activity and properties ofthe compounds disclosed herein, and does not cause significantirritation to a subject to which it is administered.

The term “subject”, as used herein, encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, humans,chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine;rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples ofnon-mammals include, but are not limited to, birds, fish and the like.Frequently the subject is a human.

The term “a subject in need of such treatment”, refers to a subjectwhich would benefit biologically, medically or in quality of life fromsuch treatment.

The term “therapeutically effective amount,” as used herein, refers toan amount which may increase the immune response, ameliorate at leastone symptom or clinical sign of a tumor and/or decrease the numberand/or size of metastases. Ameliorating at least one symptom or clinicalsign of a tumor can include a decrease in the size of a tumor,stabilization in the size or growth of a tumor, a reduction in the rateof growth of a tumor, an increase in tumor necrosis, a change in thetumor structure such as disintegration, a change in a biochemical markerassociated with decrease in tumor establishment, a decrease in tumorprogression or a decrease in tumor survival. An increase in immuneresponse refers to an increase in at least one cell-mediated immuneresponse of a cell population that includes cells of a tumor refers toan increase in at least one biochemical, histological, or immunologicalmarker associated with improvement of the immunological profile of thetumor microenvironment. Markers in which an increase in the amount ofthe marker is associated with an improvement of the immunologicalprofile of the tumor microenvironment include, but are not limited to,interferon-alpha; interferon-gamma; interferon inducible proteins;Interferon gamma-induced protein 10 (IP-10); TNF-alpha; chemokines suchas CCL2, CCL3, CCL4, CXCL2; activated T-cells; activated B-cells;activated NK-cells; tumor specific T-cells, activated tumor associatedmacrophages; chemokine receptors such as CCR6; or tumor associatedlymphoid aggregates. Markers associated with a tumor microenvironmentcan be determined, for example, by analysis of a biopsy (for exampleneedle biopsy) from the tumor, the localized tumor region, or a tumordraining lymph node. Analysis for the markers can be done using standardtechniques such as by histology (HNE stain), flow cytometry, geneexpression assays (quantitative PCR), immunochemistry techniques, aswell as other techniques commonly known to those of ordinary skill inthe art.

The term “TLR7 agonist”, as used herein, refers to a compound whichtargets or activates the biological activity of Toll-like Receptor 7(TLR7). Particularly, the “TLR7 agonist” can be a compound thatactivates TLR7 with an EC₅₀ of less than 5 μM, measured by the reportergene assay described herein, wherein Human embryonic kidney 293 (HEK293) cells were stably transfected with human TLR7. Preferably, the“TLR7 agonist” is a compound that activates TLR7 with an EC₅₀ of lessthan 1 μM, measured by the reporter gene assay described herein, whereinHuman embryonic kidney 293 (HEK 293) cells were stably transfected withhuman TLR7. The TLR7 agonists can be for example any compound describedin WO2011/049677 and the exemplary compounds described herein.

The term “treat”, “treating”, “treatment” or “therapy” as used hereincomprises a treatment relieving, reducing or alleviating at least onesymptom in a subject or effecting a delay of progression of a disease.For example, treatment can be the diminishment of one or severalsymptoms of a disorder or complete eradication of a disorder, such ascancer. Within the meaning of the present invention, the term “treat”also denotes to arrest, delay the onset (i.e., the period prior toclinical manifestation of a disease) and/or reduce the risk ofdeveloping or worsening a disease. The term “protect” is used herein tomean prevent delay or treat, or all, as appropriate, development orcontinuance or aggravation of a disease in a subject, e.g., a mammal orhuman.

The term “prevent”, “preventing” or “prevention” as used hereincomprises the prevention of at least one symptom associated with orcaused by the state, disease or disorder being prevented.

The compound names provided herein were obtained using ChemBioDraw Ultra14.0 (CambridgeSoft®).

Unless specified otherwise, the term “compounds of the presentinvention”, “compounds of the invention” or “compounds disclosed herein”refers to compounds of Fomula (A), and pharmaceutically acceptablesalts, stereoisomers (including diastereoisomers and enantiomers),tautomers and isotopically labeled compounds (including deuteriumsubstitutions) thereof.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

Description of the Invention and Preferred Embodiments PharmaceuticalCompositions

One aspect of the invention are pharmaceutical compositions comprising aTLR7 agonist, or a pharmaceutically acceptable salt thereof, one or morepharmaceutically acceptable excipients and aluminum-containingparticles. In certain embodiments of this aspect, the pharmaceuticalcompositions are liquid compositions. In certain embodiments such liquidcompositions are suspensions, while in other embodiments such liquidcompositions are solutions. In certain embodiments of this aspect, thesepharmaceutical compositions are solid compositions. In certainembodiments such solid compositions are lyophilisates, while in otherembodiments such solid compositions are spray dried powders.

Another aspect of the invention are pharmaceutical compositioncomprising a TLR7 agonist, or a pharmaceutically acceptable saltthereof, one or more pharmaceutically acceptable excipients and asuspension of aluminum-containing particles.

Another aspect of the invention are pharmaceutical compositionscomprising a TLR7 agonist and one or more pharmaceutically acceptableexcipients. In certain embodiments of this aspect, these pharmaceuticalcompositions are solid compositions. In certain embodiments such solidcompositions are lyophilisates, while in other embodiments such solidcompositions are spray dried powders.

In particular, the pharmaceutical compositions of the invention (liquidcompositions or solid compositions) comprise a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or        —C(═O)CF₂P(O)(OH)₂;    -   R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴, —OL₂R⁴, —OR⁴,        —OL₂R⁶, —OL₂L₃R⁶, —OL₂L₃L₂R⁶, —OL₂L₃R₄—OL₂L₃L₂R⁴ or —OCH₃;    -   each R³ is independently selected from H and fluoro;    -   R⁴ is —P(O)(OH)₂,    -   R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   R⁶ is —CF₂P(O)(OH)₂ or —C(O)OH;    -   L₁ is C₁-C₆alkylene, C₂-C₆alkenylene or        —((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene and        C₂-C₆alkenylene of L₁ are substituted with 0 to 4 fluoro groups;    -   each L₂ is independently selected from C₁-C₆alkylene and        —((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂        is substituted with 0 to 4 fluoro groups;    -   L₃ is arylene or a 5-6 membered heteroarylene;    -   each p is independently selected from 1, 2, 3, 4, 5 and 6, and    -   q is 1, 2, 3 or 4.    -   and wherein the compound of Formula (A) is a TLR7 agonists.

General procedures for preparing compounds of Formula (A) are describedin WO2011/049677.

In certain embodiments, compounds of Formula (A) are prepared as apharmaceutically acceptable base addition salt. Pharmaceuticallyacceptable base addition salts of compounds of Formula (A) include, butare not limited to, sodium, potassium, ammonium, calcium, magnesium,iron, silver, zinc, copper, isopropylamine, benzathine, cholinate,diethanolamine, diethylamine, lysine, arginine, meglumine, piperazine ortromethamine salt forms. Lists of additional suitable base additionsalts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20thed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002.

The pharmaceutical compositions of the invention are injectablecompositions which comprise a compound of Formula (A), or apharmaceutically acceptable salt thereof, aluminum-containing particlesand one or more pharmaceutically acceptable excipients. The compound ofFormula (A), or a pharmaceutically acceptable salt thereof, included inthe pharmaceutical compositions of the invention are present in atherapeutically effective amount. The pharmaceutically acceptableexcipients included in the pharmaceutical compositions of the inventioninclude, but are not limited to, bulking agents, lyoprotectants,buffering agent, tonicity modifier, isotonic agents, antioxidants,antimicrobial agents, antibacterial agents, antifungal agents,solubilizing agents, surfactants and wetting agents. Such excipients foruse in an injectable formulation are known to those skilled in the art(see, for example, Remington's Pharmaceutical Sciences, 18th Ed. MackPrinting Company, 1990 and Pharma Times, Vol. 45, No. 3, 2013 pp.65-77). The parenteral pharmaceutical compositions of the invention alsocomprise water as the pharmaceutically and physiologically acceptableinjectable fluid vehicle.

In general bulking agents are included in a lyophilized product toprovide bulk and structure to the lyophilzed powder, which aids indissolution of the active agent. Lyoprotectants help to stabilize andprevent the degradation of the active agent during freeze-drying andstorage. The bulking agents and lyoprotectants which may be included inthe pharmaceutical compositions of the invention include, but are nolimited to, sucrose, lactose, trehalose, mannitol, sorbitol, raffinose,glycine, histidine, polyethylene glycol and low molecular weightpolyvinyl pyrrrollidones (i.e. Povidone K12 and Povidone K17).

Buffering agents are included into pharmaceutical compositions to adjustand stabilize pH and optimize active agent solubility and stability.Buffering agents are also used in the pharmaceutical compositions of theinvention to ensure that the phosponic acid groups of the compounds ofFormula (A) are ionized (e.g. in the pH range of 7-9). The bufferingagents which may be included in the pharmaceutical compositions of theinvention include, but are no limited to, Tris, glycine, meglumine,histidine and citrate/citric acid.

Tonicity modifiers and isotonic agents are included into pharmaceuticalcompositions to maintain ensure the formulation is isotonic with humanplasma. The tonicity modifiers and isotonic agents which may be includedin the pharmaceutical compositions of the invention include, but are nolimited to, dextrose, glycerol, sodium chloride, glycerin and mannitol.

Antioxidants are used to prevent/minimize the any oxidation of activeagent or excipients during storage, whereas antimicrobial agents areused to prevent the growth of micro-organisms. The antioxidants whichmay be included in the pharmaceutical compositions of the inventioninclude, but are no limited to, ascorbic acid, acetylcysteine, sulfurousacid salts (bisulfite, metabisulfite), monothioglyercol, butylatedhydroxy toluene (BHT), butylated hydroxyanisole (BHA) and thiourea. Theantimicrobial agents which may be included in the pharmaceuticalcompositions of the invention include, but are no limited to, phenol,meta-cresol, benzyl alcohol, parabens methyl, propyl, butyl),benzalkonium chloride, chlorobutanol, thimerosal, and phenylmercuricsalts (acetate, borate, nitrate).

Solubilizing agents, which can be broadly classified into surfactantsand co-solvents, help in dissolving or increasing the active agentsolubility into the formulation. The surfactants which may be includedin the pharmaceutical compositions of the invention include, but are nolimited to, polyoxyethylene sorbitan monooleate (Tween 80), sorbitanmonooleate polyoxyethylene sorbitan monolaurate (Tween 20), lecithin,polyoxyethylene-polyoxypropylene copolymers (Pluronics). Surfactants mayalso act as wetting agents and the surfactant/wetting agents which maybe included in the pharmaceutical compositions of the invention include,but are no limited to, lecithin, Polysorbate 20, Polysorbate 80,Pluronic F-68 and Sorbitan trioleate (span 85).

The pharmaceutical compositions of the invention can be prepared usingprocesses which include admixing a compound of Formula (A), or apharmaceutically acceptable salts thereof, with one or morepharmaceutically acceptable excipients and water. Alternatively, thepharmaceutical compositions of the invention can be prepared by admixinga reconstituted lyophilisate (reconstituted with water) with a solutioncomprising an aluminum-containing particles, wherein the lyophilisatecomprises a compound of Formula (A), or a pharmaceutically acceptablesalts thereof, a buffering agent (pH 7.0 to 8.0), a bulking agent and alyoprotectant.

In another aspect, the pharmaceutical compositions of the invention canbe prepared by admixing a reconstituted lyophilisate (reconstituted withwater) with a solution comprising an aluminum-containing particles,wherein the lyophilisate comprises a compound of Formula (A), or apharmaceutically acceptable salts thereof, a buffering agent (pH 7.0 to8.0), a bulking agent, a lyoprotectant, a surfactant and a wettingagent.

The particles that comprise aluminum included in the pharmaceuticalcomposition or lyophilisate of the invention include, but are notlimited to, aluminum hydroxide, aluminum oxyhydroxide and aluminumhydroxyphosphate. Compounds of Formula (A) can bind to such particles,such as, by way of example only, aluminum hydroxide, aluminumoxyhydroxide and aluminum hydroxyphosphate. Aluminum-containingparticles have been used in vaccines to bind an antigen. A discussion ofaluminum-containing particles and their uses in vaccines is given inExpert Rev. Vaccines, 46(5), 2007, 685-698 and Vaccines, 25, 2007,6618-6624.

Certain aspects and examples of the pharmaceutical compositions of theinvention are provided in the following listing of enumeratedembodiments. It will be recognized that features specified in eachembodiment may be combined with other specified features to providefurther embodiments of the present invention.

Embodiment 1. A pharmaceutical composition comprising a TLR7 agonisthaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable excipients,wherein the compound of Formula (A) is selected from an one of thecompounds of Table 1:

TABLE 1 Com- pound Num- ber Structure Compound Name 1

(3-(2-(2-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph-thyridin-2-yl)ethyl)-3- methylphenoxy)ethoxy) ethoxy)-1,1-difluoropropyl)phosphonic acid 2

(3-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)propyl) phosphonic acid 3

4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate 4

((4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)methyl) phosphonic acid 5

5-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)-1,1- difluoropentylphosphonic acid 6

(4-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)-1,1- difluorobutyl)phosphonic acid 7

3-(2-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)- 1,1- difluoropropylphosphonic acid 8

2-(4-((4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)methyl) phenyl)-1,1- difluoroethylphosphonic acid 9

2-(5-amino-2-(4-methoxy- 2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)- 1,1-difluoro-2- oxoethylphosphonic acid 10

(E)-(2-(5-Amino-2-(4- methoxy-2- methylphenethyl)benzo[f][1,7]naphthyridin-8- yl)vinyl)phosphonic acid 11

2-(5-amino-2-(4-methoxy- 2-methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)ethylphosphonic acid 12

(E)-(2-(5-Amino-2-(4- methoxy-2- methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1- fluorovinyl)phosphonic acid 13

(3-((4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)methyl) phenyl)phosphonic acid 14

(5-amino-2-(4-methoxy- 2-methylphenethyl)benzo [f][1,7]naphthyridine-8-carbonyl)phosphonic acid 15

3-(5-amino-2-(4-(2-(3,3- difluoro-3- phosphonopropoxy) ethoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8- yl)propanoic acid 16

3-(5-amino-2-(2-methyl- 4-(3-phosphonopropoxy) phenethyl)benzo[f][1,7]naphthyridin-8-yl) propanoic acid 17

3-(5-amino-2-(4-(4,4- difluoro-4- phosphonobutoxy)-2-methylphenethyl)benzo [f][1,7]naphthyridin-8- yl)propanoic acid 18

3-(5-amino-2-(4-(2-(2- (3,3-difluoro-3- phosphonopropoxy)ethoxy)ethoxy)-2- methylphenethyl)benzo [f][1,7]naphthyridin-8-yl)propanoic acid 19

3-(5-amino-2-(2-methyl- 4-(2-(2-(2-(2- phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl) benzo[f][1,7]naphthyridin- 8-yl)propanoic acid20

3-(5-amino-2-(2-methyl- 4-(2-(2-(2- phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo [f][1,7]naphthyridin-8- yl)propanoic acid 21

3-(5-amino-2-(2-methyl- 4-(2-(2- phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7] naphthyridin-8-yl) propanoic acid 22

(2-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)ethyl) phosphonic acid 23

(6-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)hexyl) phosphonic acid 24

(6-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)-1,1- difluorohexyl)phosphonic acid 25

(4-((4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)methyl) benzyl)phosphonic acid 26

(2-(2-(2-(4-(2-(5-amino- 8-methylbenzo[f][1,7] naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy) ethoxy)ethyl)phosphonic acid 27

(5-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)pentyl) phosphonic acid 28

(4-(4-(2-(5-amino-8- methylbenzo[f][1,7]naph- thyridin-2-yl)ethyl)-3-methylphenoxy)butyl) phosphonic acid

Embodiment 2. A pharmaceutical composition comprising a TLR7 agonisthaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, aluminum-containing particles, and one or morepharmaceutically acceptable excipients, wherein the TLR7 agonist is acompound selected from any one of the compounds of Table 1.

Embodiment 3. A pharmaceutical composition comprising a TLR7 agonisthaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, aluminum-containing particles, and one or morepharmaceutically acceptable excipients, wherein the TLR7 agonist is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Embodiment 4. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients.

Embodiment 5. A lyophilisate comprising a TLR7 agonist having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,aluminum-containing particles, and one or more pharmaceuticallyacceptable excipients, wherein the TLR7 agonist is a compound selectedfrom any one of the compounds of Table 1.

Embodiment 6. A lyophilisate comprising a TLR7 agonist having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,aluminum-containing particles, and one or more pharmaceuticallyacceptable excipients, wherein the TLR7 agonist is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Embodiment 7. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, and one or more pharmaceutically acceptable excipients.

Embodiment 8. A lyophilisate comprising a TLR7 agonist having thestructure of Formula (A), or a pharmaceutically acceptable salt thereofand one or more pharmaceutically acceptable excipients, wherein the TLR7agonist is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.

Embodiment 9. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

Embodiment 10. A pharmaceutical composition comprising a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, a suspension of aluminum-containing particles, and one or morepharmaceutically acceptable excipients.

Embodiment 11. A pharmaceutical composition comprising a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, a suspension of aluminum-containing particles, and a bufferingagent.

Embodiment 12. A pharmaceutical composition comprising a compound havingthe structure of Formula (A), or a pharmaceutically acceptable saltthereof, a suspension of aluminum-containing particles, a bufferingagent, and one or more pharmaceutically acceptable excipients.

Embodiment 13. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum-containing particles, and a buffering agent, wherein thecomposition has a pH in the range of 6.5 to 9.0.

Embodiment 14. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum-containing particles, a buffering agent, and one or morepharmaceutically acceptable excipients, wherein the composition has a pHin the range of 6.5 to 9.0.

Embodiment 15. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum-containing particles, and a buffering agent, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 16. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum-containing particles, a buffering agent, and one or morepharmaceutically acceptable excipients, wherein the composition has a pHin the range of 7.0 to 8.0.

Embodiment 17. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum-containing particles, a buffering agent, and sucrose,wherein the composition has a pH in the range of 7.0 to 8.0.

Embodiment 18. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum-containing particles, a buffering agent, and mannitol,wherein the composition has a pH in the range of 7.0 to 8.0.

Embodiment 19. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum hydroxide particles, and Tris buffer, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 20. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum hydroxide particles, Tris buffer, and sucrose, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 21. A pharmaceutical composition comprising 0.5 to 2 mg/mL ofa compound of Formula (A), or a pharmaceutically acceptable saltthereof, 5-100 mM Tris buffer, 5-10% (w/v) sucrose, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,wherein the composition has a pH in the range of 7.0 to 8.0

Embodiment 22. A pharmaceutical composition comprising 0.5 to 2 mg/mL ofa compound of Formula (A), or a pharmaceutically acceptable saltthereof, 5-50 mM Tris buffer, 5-10% (w/v) sucrose, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,wherein the composition has a pH in the range of 7.0 to 8.0.

Embodiment 23. A pharmaceutical composition comprising 0.5 to 2 mg/mL ofa compound of Formula (A), or a pharmaceutically acceptable saltthereof, 5-20 mM Tris buffer, 5-10% (w/v) sucrose, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,wherein the composition has a pH in the range of 7.0 to 8.0.

Embodiment 24. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5-20 mM Tris buffer, 5-10% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 25. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 26. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 27. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.5.

Embodiment 28. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.5.

Embodiment 29. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.3.

Embodiment 30. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) sucrose, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.3.

Embodiment 31. A pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, a suspensionof aluminum hydroxide particles, Tris buffer, and mannitol, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 32. A pharmaceutical composition comprising 0.5 to 2 mg/mL ofa compound of Formula (A), or a pharmaceutically acceptable saltthereof, 5-100 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,wherein the composition has a pH in the range of 7.0 to 8.0

Embodiment 33. A pharmaceutical composition comprising 0.5 to 2 mg/mL ofa compound of Formula (A), or a pharmaceutically acceptable saltthereof, 5-50 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,wherein the composition has a pH in the range of 7.0 to 8.0.

Embodiment 34. A pharmaceutical composition comprising 0.5 to 2 mg/mL ofa compound of Formula (A), or a pharmaceutically acceptable saltthereof, 5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,wherein the composition has a pH in the range of 7.0 to 8.0.

Embodiment 35. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5-20 mM Tris buffer, 5-10% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 36. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 37. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 38. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.5.

Embodiment 39. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.5.

Embodiment 40. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,16 mM Tris buffer, 7.5% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.3.

Embodiment 41. A pharmaceutical composition comprising 1 mg/mL of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspension of aluminumhydroxide particles having an aluminum content of 2 mg/mL, wherein thecomposition has a pH of 7.5+/−0.3.

Embodiment 42. The pharmaceutical composition of any one of Embodiments10 to 41, wherein the compound of Formula (A) is a compound selectedfrom any one of the compounds of Table 1, or a pharmaceuticallyacceptable salt thereof.

Embodiment 43. The pharmaceutical composition of any one of Embodiments10 to 42, wherein the compound of Formula (A) is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid or3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof.

Embodiment 44. The pharmaceutical composition of any one of Embodiments10 to 42, wherein the compound of Formula (A) is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof.

Embodiment 45. The pharmaceutical composition of any one of Embodiments10 to 42, wherein the compound of Formula (A) is3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof.

Embodiment 46. The pharmaceutical composition of any one of Embodiments10 to 45, wherein the compound of Formula (A) is present in atherapeutically effective amount.

Embodiment 47. The pharmaceutical composition of any one of Embodiments10 to 46, wherein the composition further comprises polyethylene glycol,polyoxyethylene sorbitan monooleate (Tween 80) or Pluronic F-68.

Embodiment 48. The pharmaceutical composition of any one of Embodiments10 to 46, wherein the composition further comprises 1-2% of polyethyleneglycol, polyoxyethylene sorbitan monooleate (Tween 80) or Pluronic F-68.

Embodiment 49. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, one or morepharmaceutically acceptable excipients and a suspension ofaluminum-containing particles.

Embodiment 50. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand a suspension of aluminum-containing particles.

Embodiment 51. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agent,one or more pharmaceutically acceptable excipients and a suspension ofaluminum-containing particles.

Embodiment 52. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand a suspension of aluminum-containing particles, wherein thecomposition has a pH in the range of 6.5 to 9.0.

Embodiment 53. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agent,one or more pharmaceutically acceptable excipients and a suspension ofaluminum-containing particles, wherein the composition has a pH in therange of 6.5 to 9.0.

Embodiment 54. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand a suspension of aluminum-containing particles, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 55. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agent,one or more pharmaceutically acceptable excipients and a suspension ofaluminum-containing particles, wherein the composition has a pH in therange of 7.0 to 8.0.

Embodiment 56. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agent,sucrose and a suspension of aluminum-containing particles, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 57. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agent,mannitol and a suspension of aluminum-containing particles, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 58. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer, and asuspension of aluminum hydroxide particles.

Embodiment 59. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer,sucrose and a suspension of aluminum hydroxide particles, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 60. A pharmaceutical composition comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0 Embodiment 61. Apharmaceutical composition comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-50 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 62. A pharmaceutical composition comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 63. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) sucrose, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, wherein the compositionhas a pH in the range of 7.0 to 8.0.

Embodiment 64. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHin the range of 7.0 to 8.0.

Embodiment 65. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHin the range of 7.0 to 8.0.

Embodiment 66. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.5.

Embodiment 67. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.5.

Embodiment 68. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.3.

Embodiment 69. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) sucrose, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.3.

Embodiment 70. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer,mannitol and a suspension of aluminum hydroxide particles, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 71. A pharmaceutical composition comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0 Embodiment 72. Apharmaceutical composition comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-50 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 73. A pharmaceutical composition comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL, wherein thecomposition has a pH in the range of 7.0 to 8.0.

Embodiment 74. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, wherein the compositionhas a pH in the range of 7.0 to 8.0.

Embodiment 75. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHin the range of 7.0 to 8.0.

Embodiment 76. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHin the range of 7.0 to 8.0.

Embodiment 77. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.5.

Embodiment 78. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.5.

Embodiment 79. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.3.

Embodiment 80. A pharmaceutical composition comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, wherein the composition has a pHof 7.5+/−0.3.

Embodiment 81. The pharmaceutical composition of any one of Embodiments49 to 80, wherein the3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is present in a therapeutically effective amount.

Embodiment 82. The pharmaceutical composition of any one of Embodiments49 to 81, wherein the composition further comprises polyethylene glycol,polyoxyethylene sorbitan monooleate (Tween 80) or Pluronic F-68.

Embodiment 83. The pharmaceutical composition of any one of Embodiments49 to 81, wherein the composition further comprises 1-2% of polyethyleneglycol, polyoxyethylene sorbitan monooleate (Tween 80) or Pluronic F-68.

Embodiment 84. A lyophilisate comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

Embodiment 85. A lyophilisate comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, and a buffering agent.

Embodiment 86. A lyophilisate comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, a buffering agent and one ormore pharmaceutically acceptable excipients.

Embodiment 87. A lyophilisate comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof and Tris buffer.

Embodiment 88. A lyophilisate comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, Tris buffer and sucrose.

Embodiment 89. A lyophilisate comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, Tris buffer and mannitol.

Embodiment 90. A lyophilisate prepared from a solution having a pHbetween 6.5 and 9.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, and a buffering agent.

Embodiment 91. A lyophilisate prepared from a solution having a pHbetween 6.5 and 9.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, a buffering agent and one ormore pharmaceutically acceptable excipients.

Embodiment 92. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, and a buffering agent.

Embodiment 93. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, a buffering agent and one ormore pharmaceutically acceptable excipients.

Embodiment 94. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, a buffering agent and sucrose.

Embodiment 95. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, a buffering agent andmannitol.

Embodiment 96. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, and Tris buffer.

Embodiment 97. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, Tris buffer and sucrose.

Embodiment 98. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-100 mMTris buffer and 5-10% (w/v) sucrose.

Embodiment 99. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-50 mM Trisbuffer and 5-10% (w/v) sucrose.

Embodiment 100. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer and 5-10% (w/v) sucrose.

Embodiment 101. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of a compound of Formula (A),or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and5-10% (w/v) sucrose.

Embodiment 102. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of a compound of Formula (A),or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and7.5% (w/v) sucrose.

Embodiment 103. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of a compound of Formula (A),or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and8.25% (w/v) sucrose.

Embodiment 104. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5%(w/v) sucrose.

Embodiment 105. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25%(w/v) sucrose.

Embodiment 106. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5%(w/v) sucrose.

Embodiment 107. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25%(w/v) sucrose.

Embodiment 108. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising a compound of Formula (A), or apharmaceutically acceptable salt thereof, Tris buffer and mannitol.

Embodiment 109. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-100 mMTris buffer and 5-10% (w/v) mannitol.

Embodiment 110. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-50 mM Trisbuffer and 5-10% (w/v) mannitol.

Embodiment 111. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer and 5-10% (w/v) mannitol.

Embodiment 112. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of a compound of Formula (A),or a pharmaceutically acceptable salt thereof, 5-20 mM Tris buffer and5-10% (w/v) mannitol.

Embodiment 113. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of a compound of Formula (A),or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer and7.5% (w/v) mannitol.

Embodiment 114. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of a compound of Formula (A),or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer and8.25% (w/v) mannitol.

Embodiment 115. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5%(w/v) mannitol.

Embodiment 116. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25%(w/v) mannitol.

Embodiment 117. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 16 mM Tris buffer and 7.5%(w/v) mannitol.

Embodiment 118. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of a compound of Formula (A), or apharmaceutically acceptable salt thereof, 5 mM Tris buffer and 8.25%(w/v) mannitol.

Embodiment 119. The lyophilisate of any one of Embodiments 84 to 118,wherein the compound of Formula (A) is a compound selected from any oneof the compounds of Table 1, or a pharmaceutically acceptable saltthereof.

Embodiment 120. The lyophilisate of any one of Embodiments 84 to 118,wherein the compound of Formula (A) is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid or3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof.

Embodiment 121. The lyophilisate of any one of Embodiments 84 to 118,wherein the compound of Formula (A) is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof.

Embodiment 122. The lyophilisate of any one of Embodiments 84 to 118,wherein the compound of Formula (A) is3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof.

Embodiment 123. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

Embodiment 124. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and a bufferingagent.

Embodiment 125. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand one or more pharmaceutically acceptable excipients.

Embodiment 126. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and Tris buffer.

Embodiment 127. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer andsucrose.

Embodiment 128. A lyophilisate comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer andmannitol.

Embodiment 129. A lyophilisate prepared from a solution having a pHbetween 6.5 and 9.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and a bufferingagent.

Embodiment 130. A lyophilisate prepared from a solution having a pHbetween 6.5 and 9.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand one or more pharmaceutically acceptable excipients.

Embodiment 131. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and a bufferingagent.

Embodiment 132. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand one or more pharmaceutically acceptable excipients.

Embodiment 133. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand sucrose.

Embodiment 134. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a buffering agentand mannitol.

Embodiment 135. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and Tris buffer.

Embodiment 136. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer andsucrose.

Embodiment 137. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer and 5-10% (w/v) sucrose.

Embodiment 138. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-50 mM Tris bufferand 5-10% (w/v) sucrose.

Embodiment 139. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Tris bufferand 5-10% (w/v) sucrose.

Embodiment 140. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Tris bufferand 5-10% (w/v) sucrose.

Embodiment 141. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris bufferand 7.5% (w/v) sucrose.

Embodiment 142. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris bufferand 8.25% (w/v) sucrose.

Embodiment 143. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris bufferand 7.5% (w/v) sucrose.

Embodiment 144. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris bufferand 8.25% (w/v) sucrose.

Embodiment 145. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris bufferand 7.5% (w/v) sucrose.

Embodiment 146. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris bufferand 8.25% (w/v) sucrose.

Embodiment 147. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, Tris buffer andmannitol.

Embodiment 148. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer and 5-10% (w/v) mannitol.

Embodiment 149. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-50 mM Tris bufferand 5-10% (w/v) mannitol.

Embodiment 150. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Tris bufferand 5-10% (w/v) mannitol.

Embodiment 151. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Tris bufferand 5-10% (w/v) mannitol.

Embodiment 152. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris bufferand 7.5% (w/v) mannitol.

Embodiment 153. A lyophilisate prepared from a solution having a pHbetween 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris bufferand 8.25% (w/v) mannitol.

Embodiment 154. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris bufferand 7.5% (w/v) mannitol.

Embodiment 155. A lyophilisate prepared from a solution having a pH of7.5+/−0.5 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris bufferand 8.25% (w/v) mannitol.

Embodiment 156. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris bufferand 7.5% (w/v) mannitol.

Embodiment 157. A lyophilisate prepared from a solution having a pH of7.5+/−0.3 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris bufferand 8.25% (w/v) mannitol.

Embodiment 158. The lyophilisate of any one of Embodiments 84 to 157,further comprising aluminum-containing particles.

Embodiment 159. The lyophilisate of any one of Embodiments 84 to 157,further comprising aluminum hydroxide particles.

Embodiment 160. The lyophilisate of any one of Embodiments 84 to 159,further comprising polyethylene glycol, polyoxyethylene sorbitanmonooleate (Tween 80) or Pluronic F-68.

Embodiment 161. A pharmaceutical composition prepared by reconstitutinga lyophilisate of any one of Embodiments 84 to 157, with water andadmixing with a suspension of aluminum-containing particles having analuminum content of 1 to 4 mg/mL.

Embodiment 162. A pharmaceutical composition prepared by reconstitutinga lyophilisate of any one of Embodiments 84 to 157, with water andadmixing with a suspension of aluminum hydroxide particles having analuminum content of 1 to 4 mg/mL.

Embodiment 163. A pharmaceutical composition prepared by reconstitutinga lyophilisate of any one of Embodiments 84 to 157, with water andadmixing with a suspension of aluminum-containing particles having analuminum content of 2 mg/mL.

Embodiment 164. A pharmaceutical composition prepared by reconstitutinga lyophilisate of any one of Embodiments 84 to 157, with water andadmixing with a suspension of aluminum hydroxide particles having analuminum content of 2 mg/mL.

The aluminum-containing particles in the pharmaceutical compositions andcertain lyophilisates of the invention may be present as a suspension.In general, the aluminum-containing particles are present as a 0.1-5%suspension. In certain embodiments, the aluminum-containing particlesmay be present as a 0.1-2% suspension. The size distribution of thealuminum-containing particles may be 0.1-20 micrometers. In certainembodiments the size distribution of the aluminum-containing particlesmay be 1-20 micrometers. In certain embodiments the size distribution ofthe aluminum-containing particles may be 2-10 micrometers. In otherembodiments the aluminum-containing particles are a 0.3-0.4% suspensionwith a size distribution of 2-10 micrometers. Another embodiment is a0.4% suspension of aluminum-containing particles with a sizedistribution of 2-10 micrometers.

Byway of example, the aluminum-containing particles in thepharmaceutical compositions and certain lyophilisates of the inventionare aluminum hydroxide particles. In general the aluminum hydroxideparticles are present as a 0.1-5% suspension, but preferably as a 0.1-2%suspension. The size distribution of the aluminum hydroxide articles isgenerally 1-20 micrometers, but preferably, the size distribution of thealuminum hydroxide particles is 2-10 micrometers. A certain embodimentthe aluminum hydroxide particles are present as a 0.3-0.4% suspensionwith a size distribution of 2-10 micrometers. Another embodiment is a0.4% suspension of aluminum hydroxide particles with a size distributionof 2-10 micrometers.

In certain embodiments, the aluminum-containing particle as are aluminumhydroxide particle as and compounds of Formula (A) are bound/adsorbed toaluminum hydroxide particles.

In still other embodiments the aluminum-containing particles arealuminum hydroxide particles and the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, wherein3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is bound/adsorbed to the aluminum hydroxide particles.

Binding Efficiency of Compounds of Formula (A) to Aluminum-ContainingParticles

The compounds of Formula (A) in the pharmaceutical compositions andlyophilisates of the invention can bind to aluminum-containingparticles, such as, by way of example only, aluminum hydroxideparticles, aluminum oxyhydroxide particles and aluminum hydroxyphosphateparticles. Compounds of Formula (A) have either a phosphate or aphosphonate (ionized phosphonic acid), with certain compounds of Formula(A) having an additional ionizable groups, such as a carboxylic acid.The compounds of Formula (A) may bind/adsorb to aluminum-containingparticles via ionic interactions between the aluminium ions of thealuminum-containing particle and the phosphate or phosphonate group ofthe compound of Formula (A).

The efficiency of binding of compounds of Formula (A) to analuminum-containing particle, as reflected in the percentage (%) boundto an aluminum-containing particle, is a function of the (weight/weight)ratio of weight of compound to weight of aluminum of thealuminum-containing particles. In addition, depending on the (w/w)ratio, the binding efficiency has an apparent pH dependence.Binding/Adsorption of compounds of Formula (A) to aluminum-containingparticles is mediated via ionic charge interactions between aluminiumions and the phosphate or phosphonate group of the compound of Formula(A). Binding/Adsorption is best accomplished in the pH interval betweenthe point of zero charge (PZC) of the compound of Formula (A) and thePZC of the aluminum-containing particle. The adsorption of compounds ofFormula (A) to aluminum-containing particles is demonstrated in Example3 and Example 4. Example 4 illustrates the dependence of bindingefficiency on the (w/w) ratio of the weight of aluminum of thealuminum-containing particles to the weight of compound, and the pHdependence. Furthermore, at a fixed aluminum to compound ratio, thebinding efficiency may depend on the final concentration of the compoundof Formula (A) at values below 0.5 mg/mL.

In certain embodiments the efficiency of binding of a compound ofFormula (A) to aluminum-containing particles is 75-100%. In otherembodiments the efficiency of binding of a compound of Formula (A) toaluminum-containing particles is 80-100%. In further embodiments theefficiency of binding of a compound of Formula (A) toaluminum-containing particles is 95-100%. In further embodiments theefficiency of binding of a compound of Formula (A) toaluminum-containing particles is 97-100%. In further embodiments theefficiency of binding of a compound of Formula (A) toaluminum-containing particles is 98-100%.

In certain embodiments the aluminum-containing particles are aluminumhydroxide particles and the efficiency of binding of a compound ofFormula (A) to aluminum hydroxide particles is 75-100%. In otherembodiments the aluminum-containing particles are aluminum hydroxideparticles and the efficiency of binding of the compound of Formula (A)to aluminum hydroxide particles is 80-100%. In further embodiments thealuminum-containing particles are aluminum hydroxide particles and theefficiency of binding of the compound of Formula (A) to aluminumhydroxide particles is 95-100%. In further embodiments thealuminum-containing particles are aluminum hydroxide particles and theefficiency of binding of the compound of Formula (A) to aluminumhydroxide particles is 97-100%. In further embodiments thealuminum-containing particles are aluminum hydroxide particles and theefficiency of binding of the compound of Formula (A) to aluminumhydroxide particles is 98-100%.

In another embodiment the aluminum-containing particles are aluminumhydroxide particles and the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, wherein the efficiency of binding of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is 95-100%. In a further embodimentthe aluminum-containing particles are aluminum hydroxide particles andthe compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, wherein the efficiency of binding of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is 97-100%. In the embodiment thealuminum-containing particles are aluminum hydroxide and the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, wherein the efficiency of binding of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is 98-100%.

In general, a binding efficiency of about 75%-100% for binding of acompound of Formula (A) to an aluminum-containing particles, may beobtained with a (w/w) ratio of the weight of aluminum in thealuminum-containing particles to the weight of compound of Formula (A)in the range from about 0.8:1 to about 2.5:1. In certain embodimentsbinding efficiencies in the range of 80%-100% may be obtained with a(w/w) ratio of aluminum in the aluminum-containing particles to acompound of Formula (A) in the range from 1:1 to 2.5:1. In otherembodiments binding efficiencies in the range of 90%-100% may beobtained with a (w/w) ratio of aluminum in the aluminum-containingparticles to a compound of Formula (A) in the range from 1.25:1 to2.5:1. In other embodiments binding efficiencies in the range of97%-100% may be obtained with a (w/w) ratio of aluminum in thealuminum-containing particles to a compound of Formula (A) in the rangefrom 1.5:1 to 2.5:1. In other embodiments binding efficiencies in therange of 97%-100% may be obtained with a (w/w) ratio of aluminum in thealuminum-containing particles to a compound of Formula (A) in the rangefrom 1.5:1 to 2:1. In other embodiments binding efficiencies in therange of 98%-100% may be obtained with a (w/w) ratio of aluminum in thealuminum-containing particles to a compound of Formula (A) in the rangefrom 1.5:1 to 2:1.

In general, a binding efficiency of about 75%-100% for binding of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicto aluminum-containing particles, may be obtained with a (w/w) ratio ofthe weight of aluminum in the aluminum-containing particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from about 0.8:1 to about 2.5:1. In certain embodimentsbinding efficiencies in the range of 80%-100% may be obtained with a(w/w) ratio of the weight of aluminum in the aluminum-containingparticles to the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1:1 to 2.5:1. In other embodiments bindingefficiencies in the range of 90%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum-containing particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.25:1 to 2.5:1. In other embodiments bindingefficiencies in the range of 97%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum-containing particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.5:1 to 2.5:1. In other embodiments bindingefficiencies in the range of 97%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum-containing particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.5:1 to 2:1. In other embodiments bindingefficiencies in the range of 98%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum-containing particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.5:1 to 2:1.

In general, a binding efficiency of about 75%-100% for binding of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicto aluminum hydroxide particles, may be obtained with a (w/w) ratio ofthe weight of aluminum in the aluminum hydroxide particles to the weightof3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from about 0.8:1 to about 2.5:1. In certain embodimentsbinding efficiencies in the range of 80%-100% may be obtained with a(w/w) ratio of the weight of aluminum in the aluminum hydroxideparticles to the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1:1 to 2.5:1. In other embodiments bindingefficiencies in the range of 90%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum hydroxide particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.25:1 to 2.5:1. In other embodiments bindingefficiencies in the range of 97%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum hydroxide particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.5:1 to 2.5:1. In other embodiments bindingefficiencies in the range of 97%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum hydroxide particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.5:1 to 2:1. In other embodiments bindingefficiencies in the range of 98%-100% may be obtained with a (w/w) ratioof the weight of aluminum in the aluminum hydroxide particles to theweight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicin the range from 1.5:1 to 2:1.

A preferred (w/w) ratio of the weight of aluminum in thealuminum-containing particles to the weight of a compound of Formula (A)is 1.5:1, while the most preferred (w/w) ratio of the weight of aluminumin the aluminum-containing particles to the weight of a compound ofFormula (A) is 2:1.

A preferred (w/w) ratio of the weight of aluminum in thealuminum-containing particles to the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is 1.5:1, while the most preferred (w/w) ratio of the weight ofaluminum in the aluminum-containing particles to the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is 2:1.

A preferred (w/w) ratio of the weight of aluminum in the aluminumhydroxide particles to the weight of a compound of Formula (A) is 1.5:1,while the most preferred (w/w) ratio of the weight of aluminum in thealuminum hydroxide particles to the weight of a compound of Formula (A)is 2:1.

A preferred (w/w) ratio of the weight of aluminum in the aluminumhydroxide particles to the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is 1.5:1, while the most preferred (w/w) ratio of the weight ofaluminum in the aluminum hydroxide particles to the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is 2:1.

In certain embodiments the pH used for binding/adsorbing compounds ofFormula (A) to aluminum-containing particles is in the range of pH 6.5to pH 9.0. In certain embodiments the pH used for binding/adsorbingcompounds of Formula (A) to aluminum-containing particles is in therange of pH 7 to pH 8. In preferred embodiments the pH used forbinding/adsorbing compounds of Formula (A) to aluminum-containingparticles is in the range of pH 7.2 to pH 7.8. In preferred embodimentsthe pH used for binding/adsorbing compounds of Formula (A) toaluminum-containing particles is pH 7.5+/−0.5. In the most preferredembodiment the pH used for binding/adsorbing compounds of Formula (A) toaluminum-containing particles is pH 7.5+/−0.3.

Accordingly, the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum-containing particles is mediated via ionic chargeinteractions between aluminium ions and the phosphonate group (ionizedphosphonic acid) of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid. Thus the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid is more efficient in the pH interval between the point of zerocharge (PZC) of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid and the PZC of the aluminum-containing particle. In certainembodiments the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to an aluminum-containing particles is in the range of pH 6.5 to pH9. In certain embodiments the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to an aluminum-containing particles is in the range of pH 7 to pH8. In a more preferred embodiment the pH used for the binding/adsorptionof3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to an aluminum-containing particles is in the range of pH 7.2 to pH7.8. In preferred embodiment the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to an aluminum-containing particles is pH 7.5+/−0.5. In preferredembodiment the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to an aluminum-containing particles is pH 7.5+/−0.3.

In preferred embodiments the aluminum-containing particles are aluminumhydroxide particles and accordingly the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is mediated via ionic chargeinteractions between aluminium ions and the phosphonate group (ionizedphosphonic acid) of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid. Thus, the binding/adsorption is more efficient in the pH intervalbetween the point of zero charge (PZC) of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid and the PZC of the aluminum hydroxide particles. In certainembodiments the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is in the range of pH 6.5 to pH 9.In certain embodiments the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is in the range of pH 7 to pH 8. Ina more preferred embodiment the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide particles is in the range of pH 7.2 to pH7.8. In preferred embodiment the pH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide is pH 7.5+/−0.5. In preferred embodiment thepH used for the binding/adsorption of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to aluminum hydroxide is pH 7.5+/−0.3.

Administration-Injection Site Retention

The pharmaceutical compositions of the invention comprising a compoundof Formula (A), or a pharmaceutically acceptable salt thereof, may beadministered by injection, specifically intratumorally (intratumoralinjection), intramuscularly (intramuscular injection), intradermally(intradermal injection) or subcutaneously (subcutaneous injection). Incertain embodiments pharmaceutical compositions of the inventioncomprising a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, is administered intratumorally, while in otherembodiments, pharmaceutical compositions of the invention comprising acompound of Formula (A), or a pharmaceutically acceptable salt thereofis administered subcutaneously. In certain embodiments of intratumoraladministration the pharmaceutical compositions of the inventioncomprising a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, may be administered/injected into the peritumoral regionsurrounding a tumor. The peritumoral region may contain antitumor immunecells.

The binding of compounds of Formula (A) to aluminum-containing particlesincreases the retention of the compound of Formula (A) at the site ofinjection site, which decreases clearance of the compound and increasesthe half-life of the compound and thereby decreasing systemic exposure.In addition, retention at the tumor site may lead to improved immunepriming and reduced systemic inflammation when compared to the systemicadministration of unbound (free) compounds of Formula (A), or apharmaceutically acceptable salt thereof. Thus, the slow release of acompound of Formula (A) is considered beneficial for both efficacy andsafety because it minimizes potential systemic adverse effects by a TLR7agonist and increases drug retention in local tumor environment. Theplasma concentration-time profiles obtained after intratumoral injectionof Compound 15, either free or bound to aluminum hydroxide, are shown inExample 5 to illustrate this depot effect.

Unexpectedly it was found that systemic exposure to aluminum afteradministration of Compound 15 bound to aluminum hydroxide wassignificantly lower than systemic exposure after administration ofaluminum hydroxide alone (see Example 11).

Pharmacology and Utility

The pharmaceutical compositions of the invention may produce an immuneresponse to a tumor in a subject. Accordingly, the invention providesmethods for treating a solid tumor by producing an immune response tothe solid tumor in a subject. Additionally, the invention providesmethods for treating a liquid tumor by producing an immune response tothe tumor in a subject.

One aspect of the invention is a method for treating a solid tumor byadministering to a subject in need thereof a pharmaceutical compositionof any one of Embodiments 1 to 83 or 161 to 164.

One aspect of the invention is a method for treating a solid tumor byintratumorally administering to a subject in need thereof apharmaceutical composition of any one of Embodiments 1 to 83 or 161 to164.

One aspect of the invention is a method for treating a solid tumor byadministering to a subject in need thereof a pharmaceutical compositioncomprising a TLR7 agonist compound having the structure of Formula (A),or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients.

One aspect of the invention is a method for treating a solid tumor byadministering to a subject in need thereof a pharmaceutical compositioncomprising a TLR7 agonist compound of Table 1, or a pharmaceuticallyacceptable salt thereof, aluminum-containing particles and one or morepharmaceutically acceptable excipients.

Another aspect of the invention is the use of a pharmaceuticalcomposition of any one of Embodiments 1 to 83 or 161 to 164 for treatinga solid tumor.

Another aspect of the invention is the use of a pharmaceuticalcomposition comprising a TLR7 agonist compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof,aluminum-containing particles and one or more pharmaceuticallyacceptable excipients for treating a solid tumor.

Another aspect of the invention is the use of a pharmaceuticalcomposition comprising a TLR7 agonist compound of Table 1, or apharmaceutically acceptable salt thereof, aluminum-containing particlesand one or more pharmaceutically acceptable excipients for treating asolid tumor.

Another aspect of the invention is a pharmaceutical composition of anyone of Embodiments 1 to 83 or 161 to 164 for use in the treatment of asolid tumor.

Another aspect of the invention is a pharmaceutical compositioncomprising a TLR7 agonist compound having the structure of Formula (A),or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients for usein treating a solid tumor.

Another aspect of the invention is a pharmaceutical compositioncomprising a TLR7 agonist compound of Table 1, or a pharmaceuticallyacceptable salt thereof, aluminum-containing particles and one or morepharmaceutically acceptable excipients for use in treating a solidtumor.

The invention provides methods for treating a solid tumor byadministering, either intratumorally, intramuscularly, intradermally orsubcutaneously, a pharmaceutical composition of any one of Embodiments 1to 83 or 161 to 164.

The invention further provides methods for treating a solid tumor byadministering, either intratumorally, intramuscularly, intradermally orsubcutaneously, a pharmaceutical composition disclosed herein comprisinga compound of Formula (A), or a pharmaceutically acceptable saltthereof, aluminum-containing particles and one or more pharmaceuticallyacceptable excipients.

Another aspect of the invention is a method for treating a solid tumorby intratumorally administering to a subject in need thereof apharmaceutical composition comprising a TLR7 agonist compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,aluminum-containing particles and one or more pharmaceuticallyacceptable excipients.

Another aspect of the invention is a method for treating a solid tumorby intratumorally administering to a subject in need thereof apharmaceutical composition comprising a TLR7 agonist compound of Table1, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients.

The solid tumors which may be treatable by such methods and usesinclude, but are not limited to, a breast cancer tumor, a bladder cancertumor, a head and neck cancer tumor, a non-small cell lung cancer tumor,a small cell lung cancer tumor, a colorectal cancer tumor, agastrointestinal stromal tumor, a gastroesophageal carcinoma, a renalcell cancer tumor, a prostate cancer tumor, a liver cancer tumor, acolon cancer tumor, a pancreatic cancer tumor, an ovarian cancer tumor,a lymphoma, a cutaneous T-cell lymphoma, or a melanoma.

Large solid tumors become infiltrated by a subpopulation of myeloidderived suppressor cells (mMDSC) that suppress anti-tumor immunity. Insome embodiments, the invention provides a method for treating an immunesuppressed tumor. An immune suppressed tumor is a tumor that containsimmune suppressive associated cells such as for example T Reg cells,myeloid derived suppressor cells (MDSC), M2 macrophages, and the like orimmune suppressive factors such as inducible nitric oxide synthase(iNOS), PD-L1, and the like.

The amount of a compound of Formula (A), or a pharmaceuticallyacceptable salt thereof, incorporated in a pharmaceutical composition ofthe invention, which is the used in a method or use of the invention,may vary according to factors known in art such as for example, thephysical and clinical status of the subject, the method ofadministration, the content of the formulation, the intended dosingregimen or sequence. In consideration of such factors the appropriateamount incorporated can be readily determined by one of ordinary skillin the art. By way of example, the pharmaceutical composition of theinvention may include an amount of a compound of Formula (A), or apharmaceutically acceptable salt thereof, to provide a dose of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,to a subject from about 0.05 mg to about 5 mg. Preferably thepharmaceutical composition of the invention includes an amount of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,which provides a dose of a compound of Formula (A), or apharmaceutically acceptable salt thereof, to a subject from about 0.1 mgto about 1 mg.

With respect to duration and frequency of treatment, it is typical forskilled clinicians to monitor subjects in order to determine when thetreatment is providing therapeutic benefit, and to determine whether toincrease or decrease dosage, increase or decrease administrationfrequency, discontinue treatment, resume treatment or make otheralteration to treatment regimen.

Examples of dosing schedules for the administration of a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, adsorbed toaluminum hydroxide, either alone as a single agent or in combinationwith one or more additional therapeutic agents, are administration oncea week, twice a week, three times a week or once a month during a cycleperiod, with such administration occurring over 1, 2, 3, 4, 5, 6, 7, 8,9 or 10 cycle periods.

A cycle period is the number and timing or recommended repetitions oftherapy and are usually expressed as number of days. Examples of a cycleperiod include every 15 days, 16 days, 17 days, 18 days, 19 days, 20days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28days, 29 days, 30 days or 31 days.

A dosing schedule can include a dose delay (pause), wherein a compoundof Formula (A), or a pharmaceutically acceptable salt thereof, adsorbedto aluminum hydroxide is administered during cycle 1 and wherein acompound of Formula (A), or a pharmaceutically acceptable salt thereof,adsorbed to aluminum hydroxide is not administered during one or moresubsequent cycle periods.

By way of example, during a nine cycle dosing schedule a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, adsorbed toaluminum hydroxide is administered during cycles 1, 3, 5, 7 and 9, witha dose delay (pause) during cycles 2, 4, 6, and 8 wherein a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, adsorbed toaluminum hydroxide is not administered.

By way of another example, during an eight cycle dosing schedule acompound of Formula (A), or a pharmaceutically acceptable salt thereof,adsorbed to aluminum hydroxide is administered during cycles 1, 2, 4, 5,7 and 8, with a dose delay (pause) during cycles 3 and 6 wherein acompound of Formula (A), or a pharmaceutically acceptable salt thereof,adsorbed to aluminum hydroxide is not administered.

By way of a further example, during a six cycle dosing schedule acompound of Formula (A), or a pharmaceutically acceptable salt thereof,adsorbed to aluminum hydroxide is administered during cycles 1, 2, 5 and6, with a dose delay (pause) during cycles 3 and 4 wherein a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, adsorbed toaluminum hydroxide is not administered. By way of example a six cycledosing schedule for the administration of a compound of Formula (A), ora pharmaceutically acceptable salt thereof, adsorbed to aluminumhydroxide, either alone as a single agent or in combination with one ormore additional therapeutic agents, a compound of Formula (A), or apharmaceutically acceptable salt thereof, adsorbed to aluminum hydroxidecan be administered by intratumoral injection on Days 1 and 15 (biweeklyschedule) or Day 1 only (monthly schedule) during a 28-day cycle.Intratumoral administration occurs in Cycles 1 and 2, followed by a twocycle dosing delay (Cycles 3 and 4), and then repeat injections on Days1 and 15 (biweekly schedule) or Day 1 only (monthly schedule) for Cycles5 and 6. The dose of a compound of Formula (A), or a pharmaceuticallyacceptable salt thereof, administered during the six cycle schedule canbe from about 0.1 mg to about 1 mg, or from about 0.1 mg to about 0.6mg.

While the disclosed methods and uses of such compositions will typicallybe used to treat human subjects they may also be used to treat similaror identical diseases in other vertebrates, such as other primates,dogs, cats, horses, and cows.

Certain aspects and examples of the pharmaceutical composition uses,uses of the pharmaceutical compositions, and the methods of theinvention are provided in the following listing of additional,enumerated embodiments. It will be recognized that features specified ineach embodiment may be combined with other specified features to providefurther embodiments of the present invention.

Embodiment 165. A method for treating a solid tumor by administering toa subject in need thereof a pharmaceutical composition of any one ofEmbodiments 1 to 83 or 161 to 164.

Embodiment 166. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionof any one of Embodiments 1 to 83 or 161 to 164.

Embodiment 167. A method for treating a solid tumor by administering toa subject in need thereof a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients.

Embodiment 168. A method for treating a solid tumor by administering toa subject in need thereof a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and one or more pharmaceutically acceptable excipients.

Embodiment 169. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and one or more pharmaceutically acceptable excipients.

Embodiment 170. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 171. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles a buffering agent and one or more pharmaceutically acceptableexcipients.

Embodiment 172. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 173. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic,or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and sucrose.

Embodiment 174. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic,or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and mannitol.

Embodiment 175. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and Tris buffer.

Embodiment 176. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, Tris buffer and sucrose.

Embodiment 177. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-100 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 178. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-50 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 179. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 180. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5-20mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 181. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL ofaluminum hydroxide, 16 mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 182. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL ofaluminum hydroxide, 5 mM Tris buffer and 8.25% (w/v) sucrose.

Embodiment 183. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, Tris buffer and mannitol.

Embodiment 184. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-100 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 185. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-50 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 186. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 187. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5-20mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 188. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL ofaluminum hydroxide, 16 mM Tris buffer and 7.5% (w/v) mannitol.

Embodiment 189. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositionhaving a pH between 7.0 and 8.0 and comprising 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL ofaluminum hydroxide, 5 mM Tris buffer and 8.25% (w/v) mannitol.

Embodiment 190. Use of a pharmaceutical composition for treating a solidtumor wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients.

Embodiment 191. Use of a pharmaceutical composition for treating a solidtumor wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and one or more pharmaceutically acceptable excipients.

Embodiment 192. Use of a pharmaceutical composition for treating a solidtumor wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 193. Use of a pharmaceutical composition for treating a solidtumor wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles a buffering agent and one or more pharmaceutically acceptableexcipients.

Embodiment 194. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprisesa3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 195. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic,or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and sucrose.

Embodiment 196. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and mannitol.

Embodiment 197. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and Tris buffer.

Embodiment 198. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, Tris buffer and sucrose.

Embodiment 199. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-100 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 200. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-50 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 201. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 202. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5-20mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 203. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 16mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 204. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5 mMTris buffer and 8.25% (w/v) sucrose.

Embodiment 205. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, Tris buffer and mannitol.

Embodiment 206. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-100 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 207. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-50 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 208. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 209. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5-20mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 210. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 16mM Tris buffer and 7.5% (w/v) mannitol.

Embodiment 211. Use of a pharmaceutical composition for treating a solidtumor wherein the composition has a pH between 7.0 and 8.0 and comprises1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5 mMTris buffer and 8.25% (w/v) mannitol.

Embodiment 212. A pharmaceutical composition for use in treating a solidtumor, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and one or more pharmaceutically acceptable excipients.

Embodiment 213. A pharmaceutical composition for use in treating a solidtumor, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and one or more pharmaceutically acceptable excipients.

Embodiment 214. A pharmaceutical composition for use in treating a solidtumor, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 215. A pharmaceutical composition for use in treating a solidtumor, wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent, and one or more pharmaceuticallyacceptable excipients.

Embodiment 216. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 217. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and one or more pharmaceutically acceptableexcipients.

Embodiment 218. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles and a buffering agent.

Embodiment 219. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic,or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and sucrose.

Embodiment 220. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent and mannitol.

Embodiment 221. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles and Tris buffer.

Embodiment 222. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, Tris buffer and sucrose.

Embodiment 223. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-100 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 224. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-50 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 225. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-20 mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 226. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 1.0 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5-20mM Tris buffer and 5-10% (w/v) sucrose.

Embodiment 227. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 1.0 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 16mM Tris buffer and 7.5% (w/v) sucrose.

Embodiment 228. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 1.0 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5 mMTris buffer and 8.25% (w/v) sucrose.

Embodiment 229. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-100 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 230. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-50 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 231. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 1 to 4 mg/mL,5-20 mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 232. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 1.0 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5-20mM Tris buffer and 5-10% (w/v) mannitol.

Embodiment 233. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 1.0 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 16mM Tris buffer and 7.5% (w/v) mannitol.

Embodiment 234. A pharmaceutical composition for use in treating a solidtumor, wherein the composition has a pH between 7.0 and 8.0 andcomprises 1.0 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles having an aluminum content of 2 mg/mL, 5 mMTris buffer and 8.25% (w/v) mannitol.

Example 7 illustrates the effect on tumor volume by administration of apharmaceutical composition comprising a compound of Formula (A) with orwithout aluminum-containing particles. Specifically, Example 7illustrates the effect on tumor volume by administration of apharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid with or without aluminum-containing particles.

Combinations

The invention also provides methods for treating a solid tumor byadministering, either intratumorally, intramuscularly, intradermally orsubcutaneously, a pharmaceutically composition of any one of Embodiments1 to 83 or 161 to 164 in combination with one or more pharmaceuticalcompositions comprising another therapeutic agent. Such additionaltherapeutic agents can be a checkpoint inhibitor, a TLR9 agonist, a TLR8agonist, a TLR7 agonist, a STING agonist or a chemotherapeutic agent.

The invention further provides methods for treating a solid tumor byadministering, either intratumorally, intramuscularly, intradermally orsubcutaneously, a pharmaceutically composition disclosed hereincomprising a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, aluminum-containing particles and one or morepharmaceutically acceptable excipients in combination with one or morepharmaceutical compositions comprising another therapeutic agent. Suchadditional therapeutic agents can be a checkpoint inhibitor, a TLR9agonist, a TLR8 agonist, a TLR7 agonist, a STING agonist or achemotherapeutic agent.

General chemotherapeutic agents considered for use in combinationtherapies include anastrozole (Arimidex®), bicalutamide (Casodex®),bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection(Busulfex®), capecitabine (Xeloda®),N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®),carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®),cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®),cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomeinjection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin,polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate(Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine(Tirazone®), topotecan hydrochloride for injection (Hycamptin®),vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®),epirubicin (Ellence®), oxaliplatin (Eloxatin®), exemestane (Aromasin®),letrozole (Femara®), and fulvestrant (Faslodex®)

Combinations with Checkpoint Inhibitors

Toll-like receptors (TLRs) are a class of proteins which play anessential role in pathogen recognition and activation of the innateimmune system. To protect against autoimmunity the immune systemutilizes a family of receptors, known as checkpoint receptors, todownregulate activated immune cells, such as T-cells. A number of tumorsare able to expressing agonistic surface proteins to checkpointreceptors and thereby evade anti-tumor immune response in the tumorenvironment. In order to enable an effective anti-tumor immune responsein the tumor environment, this cloaking behavior may be overcome byblocking the checkpoint pathway by the administration of checkpointpathway inhibitors, and in conjunction activate the immune system withthe administration of a Toll-like 7 receptor agonist.

Compounds of Formula (A), or a pharmaceutically acceptable salt thereof,are TLR7 agonists and thereby activate multiple cell-mediated anti-tumorimmune responses (such as for example T-cell activation). Therefore, acombination of immune activation with a compound of Formula (A), or apharmaceutically acceptable salt thereof, and blockade of immunecheckpoint pathways with immune one or more checkpoint inhibitor(s) mayenhance and maintain an anti-tumor immune response initiated by thecompound of Formula (A), or a pharmaceutically acceptable salt thereof.Thus, the invention provides combinations of a pharmaceuticalcomposition comprising a compound of Formula (A), or a pharmaceuticallyacceptable salt thereof in combination with one or more immunecheckpoint inhibitors. Accordingly, the invention further providesmethods and uses that may be useful for treating solid tumors by theadministration of such combinations.

In particular, the invention provides combinations of a pharmaceuticalcomposition of any one of Embodiments 1 to 83 or 161 to 164 incombination with one or more pharmaceutical compositions comprising oneor more immune checkpoint inhibitors. In certain embodiments, theinvention provides a pharmaceutical composition of any one ofEmbodiments 1 to 83 or 161 to 164 further comprising one or more immunecheckpoint inhibitors.

The invention provides combinations of a pharmaceutical compositioncomprising a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, aluminum-containing particles, one or morepharmaceutically acceptable excipients in combination with one or morepharmaceutical compositions comprising one or more immune checkpointinhibitors.

The immune checkpoint inhibitor can be an inhibitor of the receptor oran inhibitor of the ligand. Immune checkpoint receptor which may betargeted by inhibitors, include but are not limited to, CytotoxicT-lymphocyte associated antigen 4 (CTLA-4), Programmed death 1 (PD-1),Lymphocyte activation gene 3 (LAG-3), T cell membrane protein 3 (TIM-3),B- and T-lymphocyte attenuator receptor (BTLA) and Killer cellimmunoglobulin-like receptors (KIR), and immune checkpoint receptorligands which may be targeted by inhibitors, include but are not limitedto, Programmed Death ligand 1 (PD-L1) and Programmed Death ligand 2(PD-L2).

The immune checkpoint inhibitor used in the combinations of theinvention can be an inhibitor of the receptor or an inhibitor of theligand. By way of example, the immune checkpoint inhibitor used in thecombinations of the invention is a CTLA-4 receptor inhibitor, a PD-1receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptorinhibitor, a BTLA receptor inhibitor, or a KIR receptor inhibitor. Inaddition, by way of example, the immune checkpoint inhibitor used in thecombinations of the invention is an inhibitor of Programmed death ligand1 (PD-L1) and/or Programmed death ligand 2 (PD-L2).

The immune checkpoint inhibitors used in the combinations of theinvention can be a low molecular weight organic molecule (molecularweight less than 1000 daltons), a peptide, a polypeptide, a protein, anantibody, an antibody fragment, or an antibody derivative. In certainembodiments, the immune checkpoint inhibitor used in the combinations ofthe invention is an antibody. In certain embodiments, the immunecheckpoint inhibitor used in the combinations of the invention theantibody is a monoclonal antibody. In certain embodiments, the immunecheckpoint inhibitor used in the combinations of the invention theantibody is a human antibody or a humanized monoclonal antibody.

In certain embodiments the immune checkpoint inhibitor used in thecombinations of the invention is an anti-CTLA-4 receptor antibody, ananti-PD-1 receptor antibody, an antiLAG-3 receptor antibody, ananti-TIM-3 receptor antibody, an anti-BTLA receptor antibody, ananti-KIR receptor antibody, an anti-PD-L1 antibody, or an anti-PD-L2antibody.

In certain embodiments the immune checkpoint inhibitor used in thecombinations of the invention is an inhibitor of the PD-L1/PD-1 pathwayor the PD-L2/PD-1 pathway.

In one embodiment, the anti-PD-L1 antibody molecule for use incombinations of the invention is one of those disclosed in U.S. PatentApplication No. 20160108123, filed Oct. 13, 2015, entitled “AntibodyMolecules to PD-L1 and Uses Thereof,” incorporated by reference in itsentirety.

In one embodiment, the anti-PD-L1 antibody includes at least one or twoheavy chain variable domain (optionally including a constant region), atleast one or two light chain variable domain (optionally including aconstant region), or both, comprising the amino acid sequence of any ofBAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05,BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10,BAP058-hum11, BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15,BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L,BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described inTable 1 of U.S. Patent Application No. 20160108123, or encoded by thenucleotide sequence in Table 1 of U.S. Patent Application No.20160108123; or a sequence substantially identical (e.g., at least 80%,85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of theaforesaid sequences.

In yet another embodiment, the anti-PD-L1 antibody molecule includes atleast one, two, or three complementarity determining regions (CDRs) froma heavy chain variable region and/or a light chain variable region of anantibody described herein, e.g., an antibody chosen from any ofBAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05,BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10,BAP058-hum11, BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15,BAP058-hum16, BAP058-hum17, BAP058-Clone-K, BAP058-Clone-L,BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described inTable 1 of U.S. Patent Application No. 20160108123, or encoded by thenucleotide sequence in Table 1 of U.S. Patent Application No.20160108123; or a sequence substantially identical (e.g., at least 80%,85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of theaforesaid sequences.

In yet another embodiment, the anti-PD-L1 antibody molecule includes atleast one, two, or three CDRs (or collectively all of the CDRs) from aheavy chain variable region comprising an amino acid sequence shown inTable 1 of U.S. Patent Application No. 20160108123, or encoded by anucleotide sequence shown in Table 1 of U.S. Patent Application No.20160108123. In one embodiment, one or more of the CDRs (or collectivelyall of the CDRs) have one, two, three, four, five, six or more changes,e.g., amino acid substitutions or deletions, relative to the amino acidsequence shown in Table 1 of U.S. Patent Application No. 20160108123, orencoded by a nucleotide sequence shown in Table 1 of U.S. PatentApplication No. 20160108123.

In yet another embodiment, the anti-PD-L1 antibody molecule includes atleast one, two, or three CDRs (or collectively all of the CDRs) from alight chain variable region comprising an amino acid sequence shown inTable 1 of U.S. Patent Application No. 20160108123, or encoded by anucleotide sequence shown in Table 1 of U.S. Patent Application No.20160108123. In one embodiment, one or more of the CDRs (or collectivelyall of the CDRs) have one, two, three, four, five, six or more changes,e.g., amino acid substitutions or deletions, relative to the amino acidsequence shown in Table 1 of U.S. Patent Application No. 20160108123, orencoded by a nucleotide sequence shown in Table 1 of U.S. PatentApplication No. 20160108123. In certain embodiments, the anti-PD-L1antibody molecule includes a substitution in a light chain CDR, e.g.,one or more substitutions in a CDR1, CDR2 and/or CDR3 of the lightchain.

In another embodiment, the anti-PD-L1 antibody molecule includes atleast one, two, three, four, five or six CDRs (or collectively all ofthe CDRs) from a heavy and light chain variable region comprising anamino acid sequence shown in Table 1 of U.S. Patent Application No.20160108123, or encoded by a nucleotide sequence shown in Table 1 ofU.S. Patent Application No. 20160108123. In one embodiment, one or moreof the CDRs (or collectively all of the CDRs) have one, two, three,four, five, six or more changes, e.g., amino acid substitutions ordeletions, relative to the amino acid sequence shown in Table 1 of U.S.Patent Application No. 20160108123, or encoded by a nucleotide sequenceshown in Table 1 of U.S. Patent Application No. 20160108123.

In one embodiment, the anti-PD-L1 antibody molecule includes at leastone, two or three CDRs or hypervariable loops from a heavy chainvariable region of an antibody described herein, e.g., an antibodychosen from any of BAP058-hum01, BAP058-hum02, BAP058-hum03,BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08,BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058-hum13,BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Clone-K,BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O,according to the Kabat and Chothia definition (e.g., at least one, two,or three CDRs or hypervariable loops according to the Kabat and Chothiadefinition as set out in Table 1 of U.S. Patent Application No.20160108123); or encoded by the nucleotide sequence in Table 1 of U.S.Patent Application No. 20160108123; or a sequence substantiallyidentical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% orhigher identical) to any of the aforesaid sequences; or which have atleast one amino acid alteration, but not more than two, three or fouralterations (e.g., substitutions, deletions, or insertions, e.g.,conservative substitutions) relative to one, two, or three CDRs orhypervariable loops according to Kabat and/or Chothia shown in Table 1of U.S. Patent Application No. 20160108123.

In one embodiment, the anti-PD-L1 antibody molecule can include VH CDR1according to Kabat et al. ((1991), “Sequences of Proteins ofImmunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, MD) or VH hypervariable loop 1 accordingto Chothia et al. (1992) J. Mol. Biol. 227:799-817, or a combinationthereof, e.g., as shown in Table 1 of U.S. Patent Application No.20160108123. In one embodiment, the combination of Kabat and Chothia CDRof VHCDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO:1, oran amino acid sequence substantially identical thereto (e.g., having atleast one amino acid alteration, but not more than two, three or fouralterations (e.g., substitutions, deletions, or insertions, e.g.,conservative substitutions)). The anti-PD-L1 antibody molecule canfurther include, e.g., VH CDRs 2-3 according to Kabat et al. and VL CDRs1-3 according to Kabat et al., e.g., as shown in Table 1 of U.S. PatentApplication No. 20160108123.

In a preferred embodiment, the anti PD-L1 antibody molecule for use inthe combinations, methods and compositions of the invention comprises(see Table 2):

-   -   (a) a heavy chain variable region (VH) comprising a VHCDR1 amino        acid sequence of SEQ ID NO:5, a VHCDR2 amino acid sequence of        SEQ ID NO:6, and a VHCDR3 amino acid sequence of SEQ ID NO:4;        and a light chain variable region (VL) comprising a VLCDR1 amino        acid sequence of SEQ ID NO:14, a VLCDR2 amino acid sequence of        SEQ ID NO:15, and a VLCDR3 amino acid sequence of SEQ ID NO:16;    -   (b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO:2;        a VHCDR2 amino acid sequence of SEQ ID NO:3; and a VHCDR3 amino        acid sequence of SEQ ID NO:4; and a VL comprising a VLCDR1 amino        acid sequence of SEQ ID NO:11, a VLCDR2 amino acid sequence of        SEQ ID NO:12, and a VLCDR3 amino acid sequence of SEQ ID NO:13;    -   (c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO:1,        a VHCDR2 amino acid sequence of SEQ ID NO:6, and a VHCDR3 amino        acid sequence of SEQ ID NO:4; and a VL comprising a VLCDR1 amino        acid sequence of SEQ ID NO:14, a VLCDR2 amino acid sequence of        SEQ ID NO:15, and a VLCDR3 amino acid sequence of SEQ ID NO:16;        or    -   (d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO:1;        a VHCDR2 amino acid sequence of SEQ ID NO:3; and a VHCDR3 amino        acid sequence of SEQ ID NO:4; and a VL comprising a VLCDR1 amino        acid sequence of SEQ ID NO:11, a VLCDR2 amino acid sequence of        SEQ ID NO:12, and a VLCDR3 amino acid sequence of SEQ ID NO:13.

In one aspect the anti-PD-L1 antibody molecule used in the combinationsof the invention comprises:

-   -   (a) a heavy chain variable domain comprising the amino acid        sequence of SEQ ID NO:7 and a light chain variable domain        comprising the amino acid sequence of SEQ ID NO:17.

TABLE 2 Amino acid and nucleotide sequences for humanized mAbsBAP058-hum013. The amino acid and nucleotide sequencesof the heavy and light chain CDRs, the heavy and lightchain variable regions, and the heavy and light chains are shown.BAP058-hum13-HC SEQ ID NO: 2 (Kabat) HCDR1 SYWMY SEQ ID NO: 3 (Kabat)HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 4 (Kabat) HCDR3 DYRKGLYAMDYSEQ ID NO: 5 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 6 (Chothia) HCDR2 DPNSGSSEQ ID NO: 4 (Chothia) HCDR3 DYRKGLYAMDY SEQ ID NO: 7 VHEVQLVQSGAEVKKPGATVKISCKVSGYTFT SYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAE DTAVYYCARDYRKGLYAMDYWGQGTTVTV SSSEQ ID NO: 8 DNA VH GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCTACAGTGAA AATCTCCTGCAAGGTTTCTGGCTACACCTTCACCAGTTACTGGATGTACTGGGTGCGAC AGGCTCGTGGACAACGCCTTGAGTGGATAGGTAGGATTGATCCTAATAGTGGGAGTAC TAAGTACAATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAACA CGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTG CAAGGGACTATAGAAAGGGGCTCTATGCTATGGACTACTGGGGCCAGGGCACCACCG TGACCGTGTCCTCC SEQ ID NO: 9 HeavyEVQLVQSGAEVKKPGATVKISCKVSGYTFT Chain SYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAE DTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 10 DNA HeavyGAGGTCCAGCTGGTACAGTCTGGGGCTG Chain AGGTGAAGAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGCTACACCTT CACCAGTTACTGGATGTACTGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATA GGTAGGATTGATCCTAATAGTGGGAGTACTAAGTACAATGAGAAGTTCAAGAACAGATT CACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGA GCCGAGGACACGGCCGTGTATTACTGTGCAAGGGACTATAGAAAGGGGCTCTATGCT ATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGC CCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCC CTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA GGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAA ATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCA CGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACG TGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAAC AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGC AAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCA TCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCC AGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACC CCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGA CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCG TGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP058-hum13-LC SEQ ID NO: 11 (Kabat) LCDR1KASQDVGTAVA SEQ ID NO: 12 (Kabat) LCDR2 WASTRHT SEQ ID NO: 13 (Kabat)LCDR3 QQYNSYPLT SEQ ID NO: 14 (Chothia) LCDR1 SQDVGTASEQ ID NO: 15 (Chothia) LCDR2 WAS SEQ ID NO: 16 (Chothia) LCDR3 YNSYPLSEQ ID NO: 17 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSR FSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 18 DNA VL GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCAAGGCCAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTGCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCTATTGGGCATCCACCCGGCACACTGGGGT CCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGC CTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATAACAGCTATCCTCTCA CGTTCGGCCAAGGGACCAAGGTGGAAAT CAAASEQ ID NO: 19 Light Chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSR FSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRG ECSEQ ID NO: 20 DNA Light GCCATCCAGTTGACCCAGTCTCCATCCTC ChainCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCAAGGCCAGTCAGGATGTGGGTACTGCTGTAGCCTGGTACCTGCAGAA GCCAGGGCAGTCTCCACAGCTCCTGATCTATTGGGCATCCACCCGGCACACTGGGGT CCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGC CTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATAACAGCTATCCTCTCA CGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGG GGAGAGTGT

In one embodiment, the PD-1 inhibitor partner of a combination of theinvention is an anti-PD-1 antibody molecule. In one embodiment, the PD-1inhibitor is an anti-PD-1 antibody molecule as described in US2015/0210769, published on Jul. 30, 2015, entitled “Antibody Moleculesto PD-1 and Uses Thereof,” incorporated by reference in its entirety.

In one embodiment, the anti-PD-1 antibody molecule comprises at leastone, two, three, four, five or six complementarity determining regions(CDRs) (or collectively all of the CDRs) from a heavy and light chainvariable region comprising an amino acid sequence shown in Table 3(e.g., from the heavy and light chain variable region sequences ofBAP049-Clone-E or BAP049-Clone-B disclosed in Table 3), or encoded by anucleotide sequence shown in Table 3. In some embodiments, the CDRs areaccording to the Kabat definition (e.g., as set out in Table 3). In someembodiments, the CDRs are according to the Chothia definition (e.g., asset out in Table 3). In some embodiments, the CDRs are according to thecombined CDR definitions of both Kabat and Chothia (e.g., as set out inTable 3). In one embodiment, the combination of Kabat and Chothia CDR ofVHCDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 21). Inone embodiment, one or more of the CDRs (or collectively all of theCDRs) have one, two, three, four, five, six or more changes, e.g., aminoacid substitutions (e.g., conservative amino acid substitutions) ordeletions, relative to an amino acid sequence shown in Table 1, orencoded by a nucleotide sequence shown in Table 3.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavychain variable region (VH) comprising a VHCDR1 amino acid sequence ofSEQ ID NO: 22, a VHCDR2 amino acid sequence of SEQ ID NO: 23, and aVHCDR3 amino acid sequence of SEQ ID NO: 24; and a light chain variableregion (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 31, aVLCDR2 amino acid sequence of SEQ ID NO: 32, and a VLCDR3 amino acidsequence of SEQ ID NO: 33, each disclosed in Table 3.

In one embodiment, the antibody molecule comprises a VH comprising aVHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 45, a VHCDR2encoded by the nucleotide sequence of SEQ ID NO: 46, and a VHCDR3encoded by the nucleotide sequence of SEQ ID NO: 47; and a VL comprisinga VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 50, a VLCDR2encoded by the nucleotide sequence of SEQ ID NO: 51, and a VLCDR3encoded by the nucleotide sequence of SEQ ID NO: 52, each disclosed inTable 3.

In one embodiment, the anti-PD-1 antibody molecule comprises a VHcomprising the amino acid sequence of SEQ ID NO: 27, or an amino acidsequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ IDNO: 27. In one embodiment, the anti-PD-1 antibody molecule comprises aVL comprising the amino acid sequence of SEQ ID NO: 41, or an amino acidsequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ IDNO: 41. In one embodiment, the anti-PD-1 antibody molecule comprises aVL comprising the amino acid sequence of SEQ ID NO: 37, or an amino acidsequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ IDNO: 37. In one embodiment, the anti-PD-1 antibody molecule comprises aVH comprising the amino acid sequence of SEQ ID NO: 27 and a VLcomprising the amino acid sequence of SEQ ID NO: 41. In one embodiment,the anti-PD-1 antibody molecule comprises a VH comprising the amino acidsequence of SEQ ID NO: 27 and a VL comprising the amino acid sequence ofSEQ ID NO: 37.

In one embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 28, or a nucleotide sequence at least85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 28. In oneembodiment, the antibody molecule comprises a VL encoded by thenucleotide sequence of SEQ ID NO: 42 or 38, or a nucleotide sequence atleast 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 42 or 38.In one embodiment, the antibody molecule comprises a VH encoded by thenucleotide sequence of SEQ ID NO: 28 and a VL encoded by the nucleotidesequence of SEQ ID NO: 42 or 38.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavychain comprising the amino acid sequence of SEQ ID NO: 29, or an aminoacid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQID NO: 29. In one embodiment, the anti-PD-1 antibody molecule comprisesa light chain comprising the amino acid sequence of SEQ ID NO: 43, or anamino acid sequence at least 85%, 90%, 95%, or 99% identical or higherto SEQ ID NO: 43. In one embodiment, the anti-PD-1 antibody moleculecomprises a light chain comprising the amino acid sequence of SEQ ID NO:39, or an amino acid sequence at least 85%, 90%, 95%, or 99% identicalor higher to SEQ ID NO: 39. In one embodiment, the anti-PD-1 antibodymolecule comprises a heavy chain comprising the amino acid sequence ofSEQ ID NO: 29 and a light chain comprising the amino acid sequence ofSEQ ID NO: 43. In one embodiment, the anti-PD-1 antibody moleculecomprises a heavy chain comprising the amino acid sequence of SEQ ID NO:29 and a light chain comprising the amino acid sequence of SEQ ID NO:39.

In one embodiment, the antibody molecule comprises a heavy chain encodedby the nucleotide sequence of SEQ ID NO: 30, or a nucleotide sequence atleast 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 30. In oneembodiment, the antibody molecule comprises a light chain encoded by thenucleotide sequence of SEQ ID NO: 44 or 40, or a nucleotide sequence atleast 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 44 or 40.In one embodiment, the antibody molecule comprises a heavy chain encodedby the nucleotide sequence of SEQ ID NO: 30 and a light chain encoded bythe nucleotide sequence of SEQ ID NO: 44 or 40.

The antibody molecules described herein can be made by vectors, hostcells, and methods described in US 2015/0210769, incorporated byreference in its entirety.

The VH and VL regions can be subdivided into regions ofhypervariability, termed “complementarity determining regions” (CDR),interspersed with regions that are more conserved, termed “frameworkregions” (FR or FW).

The extent of the framework region and CDRs has been precisely definedby a number of methods (see, Kabat, E. A., et al. (1991) Sequences ofProteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242; Chothia, C. etal. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used byOxford Molecular's AbM antibody modeling software. See, generally, e.g.,Protein Sequence and Structure Analysis of Antibody Variable Domains.In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R.,Springer-Verlag, Heidelberg).

The terms “complementarity determining region,” and “CDR,” as usedherein refer to the sequences of amino acids within antibody variableregions which confer antigen specificity and binding affinity. Ingeneral, there are three CDRs in each heavy chain variable region(HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region(LCDR1, LCDR2, LCDR3).

The precise amino acid sequence boundaries of a given CDR can bedetermined using any of a number of well-known schemes, including thosedescribed by Kabat et al. (1991), “Sequences of Proteins ofImmunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, MD (“Kabat” numbering scheme),Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numberingscheme). As used herein, the CDRs defined according the “Chothia” numberscheme are also sometimes referred to as “hypervariable loops.”

For example, under Kabat, the CDR amino acid residues in the heavy chainvariable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3); and the CDR amino acid residues in the light chainvariable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and89-97 (LCDR3). Under Chothia the CDR amino acids in the VH are numbered26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acidresidues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96(LCDR3). By combining the CDR definitions of both Kabat and Chothia, theCDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56(LCDR2), and 89-97 (LCDR3) in human VL.

Generally, unless specifically indicated, the anti-PD-1 antibodymolecules can include any combination of one or more Kabat CDRs and/orChothia CDRs, e.g., described in Table 3. In one embodiment, thefollowing definitions are used for the anti-PD-1 antibody moleculesdescribed in Table 3: HCDR1 according to the combined CDR definitions ofboth Kabat and Chothia, and HCCDRs 2-3 and LCCDRs 1-3 according the CDRdefinition of Kabat. Under all definitions, each VH and VL typicallyincludes three CDRs and four FRs, arranged from amino-terminus tocarboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3,CDR3, FR4.

Calculations of homology or sequence identity between sequences (theterms are used interchangeably herein) are performed as follows.

To determine the percent identity of two amino acid sequences, or of twonucleic acid sequences, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in one or both of a first and asecond amino acid or nucleic acid sequence for optimal alignment andnon-homologous sequences can be disregarded for comparison purposes). Ina preferred embodiment, the length of a reference sequence aligned forcomparison purposes is at least 30%, preferably at least 40%, morepreferably at least 50%, 60%, and even more preferably at least 70%,80%, 90%, 100% of the length of the reference sequence. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”).

The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunsch((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporatedinto the GAP program in the GCG software package (available atwww.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and agap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3,4, 5, or 6. In yet another preferred embodiment, the percent identitybetween two nucleotide sequences is determined using the GAP program inthe GCG software package (available at www.gcg.com), using aNWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and alength weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set ofparameters (and the one that should be used unless otherwise specified)are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extendpenalty of 4, and a frameshift gap penalty of 5.

The percent identity between two amino acid or nucleotide sequences canbe determined using the algorithm of E. Meyers and W. Miller ((1989)CABIOS, 4:11-17) which has been incorporated into the ALIGN program(version 2.0), using a PAM120 weight residue table, a gap length penaltyof 12 and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a“query sequence” to perform a search against public databases to, forexample, identify other family members or related sequences. Suchsearches can be performed using the NBLAST and XBLAST programs (version2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLASTnucleotide searches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to a nucleicacid molecule of the invention. BLAST protein searches can be performedwith the XBLAST program, score=50, wordlength=3 to obtain amino acidsequences homologous to protein molecules of the invention. To obtaingapped alignments for comparison purposes, Gapped BLAST can be utilizedas described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402.When utilizing BLAST and Gapped BLAST programs, the default parametersof the respective programs (e.g., XBLAST and NBLAST) can be used.Seewww.ncbi.nlm.nih.gov.

A “conservative amino acid substitution” is one in which the amino acidresidue is replaced with an amino acid residue having a similar sidechain. Families of amino acid residues having similar side chains havebeen defined in the art. These families include amino acids with basicside chains (e.g., lysine, arginine, histidine), acidic side chains(e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g.,glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine),nonpolar side chains (e.g., alanine, valine, leucine, isoleucine,proline, phenylalanine, methionine, tryptophan), beta-branched sidechains (e.g., threonine, valine, isoleucine) and aromatic side chains(e.g., tyrosine, phenylalanine, tryptophan, histidine).

TABLE 3 Amino acid and nucleotide sequences of exemplaryanti-PD-1 antibody molecules BAP049-Clone-B HC SEQ ID NO: 22 (Kabat)HCDR1 TYWMH SEQ ID NO: 23 (Kabat) HCDR2 NIYPGTGGSNFDEKFKNSEQ ID NO: 24 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 25 (Chothia) HCDR1GYTFTTY SEQ ID NO: 26 (Chothia) HCDR2 YPGTGG SEQ ID NO: 24 (Chothia)HCDR3 WTTGTGAY SEQ ID NO: 27 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYP GTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAY WGQGTTVTVSS SEQ ID NO: 28 DNA VHGAGGTGCAGCTGGTGCAGTCAGGCG CCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTC AAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTT CGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGC ACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACT ACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTA CCGTGACCGTGTCTAGC SEQ ID NO: 29 HCEVQLVQSGAEVKKPGESLRISCKGSGY TFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAY MELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSR STSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGSEQ ID NO: 30 DNA HC GAGGTGCAGCTGGTGCAGTCAGGCG CCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTC AAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTT CGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGC ACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACT ACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTA CCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGG CACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGT CAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCT GACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTAC TCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCT ACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGT CGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTC GGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGA TTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGA TCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGC CAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTC CGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTG CAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAA GCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAG GAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTA CCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAAC TACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTC GCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGT TCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCC TCTCCCTGGGA BAP049-Clone-B LCSEQ ID NO: 31 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 32 (Kabat)LCDR2 WASTRES SEQ ID NO: 33 (Kabat) LCDR3 QNDYSYPYTSEQ ID NO: 34 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 35 (Chothia)LCDR2 WAS SEQ ID NO: 36 (Chothia) LCDR3 DYSYPY SEQ ID NO: 37 VLEIVLTQSPATLSLSPGERATLSCKSSQS LLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTIS SLQPEDIATYYCQNDYSYPYTFGQGTK VEIKSEQ ID NO: 38 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAG CGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATC AGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCT GCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGC GGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGCAGCCCG AGGATATCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTC GGTCAAGGCACTAAGGTCGAGATTAA G SEQ ID NO: 39LC EIVLTQSPATLSLSPGERATLSCKSSQS LLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTIS SLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNR GECSEQ ID NO: 40 DNA LC GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAG CGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATC AGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCT GCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGC GGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGCAGCCCG AGGATATCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTC GGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCA GGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAG GCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGC CTGTCCAGCCCCGTGACCAAGAGCTT CAACAGGGGCGAGTGCBAP049-Clone-E HC SEQ ID NO: 22 (Kabat) HCDR1 TYWMHSEQ ID NO: 23 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 24 (Kabat)HCDR3 WTTGTGAY SEQ ID NO: 25 (Chothia) HCDR1 GYTFTTYSEQ ID NO: 26 (Chothia) HCDR2 YPGTGG SEQ ID NO: 24 (Chothia) HCDR3WTTGTGAY SEQ ID NO: 27 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYP GTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAY WGQGTTVTVSS SEQ ID NO: 28 DNA VHGAGGTGCAGCTGGTGCAGTCAGGCG CCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTC AAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTT CGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGC ACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACT ACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTA CCGTGACCGTGTCTAGC SEQ ID NO: 29 HCEVQLVQSGAEVKKPGESLRISCKGSGY TFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAY MELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSR STSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGSEQ ID NO: 30 DNA HC GAGGTGCAGCTGGTGCAGTCAGGCG CCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAG GCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTC AAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTT CGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGC ACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACT ACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTA CCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGG CACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGT CAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCT GACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTAC TCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCT ACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGT CGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTC GGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGA TTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGA TCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGC CAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTC CGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTG CAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAA GCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAG GAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTA CCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAAC TACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTC GCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGT TCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCC TCTCCCTGGGA BAP049-Clone-E LCSEQ ID NO: 31 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 32 (Kabat)LCDR2 WASTRES SEQ ID NO: 33 (Kabat) LCDR3 QNDYSYPYTSEQ ID NO: 34 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 35 (Chothia)LCDR2 WAS SEQ ID NO: 36 (Chothia) LCDR3 DYSYPY SEQ ID NO: 41 VLEIVLTQSPATLSLSPGERATLSCKSSQS LLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTIS SLEAEDAATYYCQNDYSYPYTFGQGTK VEIKSEQ ID NO: 42 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAG CGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATC AGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACT GCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGC GGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGGAAGCCG AGGACGCCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTC GGTCAAGGCACTAAGGTCGAGATTAA G SEQ ID NO: 43LC EIVLTQSPATLSLSPGERATLSCKSSQS LLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTIS SLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFlFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNR GECSEQ ID NO: 44 DNA LC GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAG CGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATC AGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACT GCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGC GGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGGAAGCCG AGGACGCCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTC GGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTG GTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCA GGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAG GCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGC CTGTCCAGCCCCGTGACCAAGAGCTT CAACAGGGGCGAGTGCBAP049-Clone-B HC SEQ ID NO: 45 (Kabat) HCDR1 ACCTACTGGATGCACSEQ ID NO: 46 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 47 (Kabat) HCDR3TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 48 (Chothia) HCDR1GGCTACACCTTCACTACCTAC SEQ ID NO: 49 (Chothia) HCDR2 TACCCCGGCACCGGCGGCSEQ ID NO: 47 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC BAP049-Clone-B LCSEQ ID NO: 50 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 51 (Kabat) LCDR2TGGGCCTCTACTAGAGAATCA SEQ ID NO: 52 (Kabat) LCDR3CAGAACGACTATAGCTACCCCTACAC C SEQ ID NO: 53 (Chothia) LCDR1AGTCAGTCACTGCTGGATAGCGGTAA TCAGAAGAACTTC SEQ ID NO: 54 (Chothia) LCDR2TGGGCCTCT SEQ ID NO: 55 (Chothia) LCDR3 GACTATAGCTACCCCTACBAP049-Clone-E HC SEQ ID NO: 45 (Kabat) HCDR1 ACCTACTGGATGCACSEQ ID NO: 46 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 47 (Kabat) HCDR3TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 48 (Chothia) HCDR1GGCTACACCTTCACTACCTAC SEQ ID NO: 49 (Chothia) HCDR2 TACCCCGGCACCGGCGGCSEQ ID NO: 47 (Chothia) HCDR3 TGGACTACCGGCACAGGCGCCTAC BAP049-Clone-E LCSEQ ID NO: 50 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 51 (Kabat) LCDR2TGGGCCTCTACTAGAGAATCA SEQ ID NO: 52 (Kabat) LCDR3CAGAACGACTATAGCTACCCCTACAC C SEQ ID NO: 53 (Chothia) LCDR1AGTCAGTCACTGCTGGATAGCGGTAA TCAGAAGAACTTC SEQ ID NO: 54 (Chothia) LCDR2TGGGCCTCT SEQ ID NO: 55 (Chothia) LCDR3 GACTATAGCTACCCCTAC

In a preferred embodiment, the anti PD-1 antibody for use in thecombinations, methods and compositions of the invention comprises:

-   -   (a) a heavy chain variable region (VH) comprising a VHCDR1 amino        acid sequence of SEQ ID NO: 25, a VHCDR2 amino acid sequence of        SEQ ID NO: 26, and a VHCDR3 amino acid sequence of SEQ ID NO:        24; and a light chain variable region (VL) comprising a VLCDR1        amino acid sequence of SEQ ID NO: 34, a VLCDR2 amino acid        sequence of SEQ ID NO: 35, and a VLCDR3 amino acid sequence of        SEQ ID NO: 36;    -   (b) a heavy chain variable region (VH) comprising a VHCDR1 amino        acid sequence of SEQ ID NO: 22; a VHCDR2 amino acid sequence of        SEQ ID NO: 23; and a VHCDR3 amino acid sequence of SEQ ID NO:        24; and a light chain variable region (VL) comprising a VLCDR1        amino acid sequence of SEQ ID NO: 31, a VLCDR2 amino acid        sequence of SEQ ID NO: 32, and a VLCDR3 amino acid sequence of        SEQ ID NO: 33;    -   (c) a heavy chain variable region (VH) comprising a VHCDR1 amino        acid sequence of SEQ ID NO: 21, a VHCDR2 amino acid sequence of        SEQ ID NO: 26, and a VHCDR3 amino acid sequence of SEQ ID NO:        24; and a a light chain variable region (VL) comprising a VLCDR1        amino acid sequence of SEQ ID NO: 34, a VLCDR2 amino acid        sequence of SEQ ID NO: 35, and a VLCDR3 amino acid sequence of        SEQ ID NO: 36; or    -   (d) a heavy chain variable region (VH) comprising a VHCDR1 amino        acid sequence of SEQ ID NO: 21; a VHCDR2 amino acid sequence of        SEQ ID NO: 23; and a VHCDR3 amino acid sequence of SEQ ID NO:        24; and a a light chain variable region (VL) comprising a VLCDR1        amino acid sequence of SEQ ID NO: 31, a VLCDR2 amino acid        sequence of SEQ ID NO: 32, and a VLCDR3 amino acid sequence of        SEQ ID NO: 33,

In another preferred embodiment, the anti PD-1 antibody for use in thecombinations, methods and compositions of the invention comprises a VHcomprising the amino acid sequence of SEQ ID NO: 27 and a VL comprisingthe amino acid sequence of SEQ ID NO: 41.

In another preferred embodiment, the anti PD-1 antibody for use in thecombinations, methods and compositions of the invention comprises a VHcomprising the amino acid sequence of SEQ ID NO: 27 and a VL comprisingthe amino acid sequence of SEQ ID NO: 37.

In another preferred embodiment, the anti PD-1 antibody for use in thecombinations, methods and compositions of the invention comprises aheavy chain comprising the amino acid sequence of SEQ ID NO: 29 and alight chain comprising the amino acid sequence of SEQ ID NO: 43.

In another preferred embodiment, the anti PD-1 antibody for use in thecombinations, methods and compositions of the invention comprises aheavy chain comprising the amino acid sequence of SEQ ID NO: 29 and alight chain comprising the amino acid sequence of SEQ ID NO: 39.

Other Exemplary PD-1 Inhibitors for Use in the Combinations DescribedHerein

In one embodiment, the anti-PD-1 antibody molecule is Nivolumab(Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538,BMS-936558, or OPDIVO®. Nivolumab (clone 5C4) and other anti-PD-1antibodies are disclosed in U.S. Pat. No. 8,008,449 and WO 2006/121168,incorporated by reference in their entirety. In one embodiment, theanti-PD-1 antibody molecule comprises one or more of the CDR sequences(or collectively all of the CDR sequences), the heavy chain or lightchain variable region sequence, or the heavy chain or light chainsequence of Nivolumab, e.g., as disclosed in Table 4.

In one embodiment, the anti-PD-1 antibody molecule is Pembrolizumab(Merck & Co), also known as Lambrolizumab, MK-3475, MK03475, SCH-900475,or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosedin Hamid, O. et al. (2013) New England Journal of Medicine 369 (2):134-44, U.S. Pat. No. 8,354,509, and WO 2009/114335, incorporated byreference in their entirety. In one embodiment, the anti-PD-1 antibodymolecule comprises one or more of the CDR sequences (or collectively allof the CDR sequences), the heavy chain or light chain variable regionsequence, or the heavy chain or light chain sequence of Pembrolizumab,e.g., as disclosed in Table 4.

In one embodiment, the anti-PD-1 antibody molecule is Pidilizumab(CureTech), also known as CT-011. Pidilizumab and other anti-PD-1antibodies are disclosed in Rosenblatt, J. et al. (2011) J Immunotherapy34(5): 409-18, U.S. Pat. Nos. 7,695,715, 7,332,582, and 8,686,119,incorporated by reference in their entirety. In one embodiment, theanti-PD-1 antibody molecule comprises one or more of the CDR sequences(or collectively all of the CDR sequences), the heavy chain or lightchain variable region sequence, or the heavy chain or light chainsequence of Pidilizumab, e.g., as disclosed in Table 4.

In one embodiment, the anti-PD-1 antibody molecule is MEDI0680(Medimmune), also known as AMP-514. MEDI0680 and other anti-PD-1antibodies are disclosed in U.S. Pat. No. 9,205,148 and WO 2012/145493,incorporated by reference in their entirety. In one embodiment, theanti-PD-1 antibody molecule comprises one or more of the CDR sequences(or collectively all of the CDR sequences), the heavy chain or lightchain variable region sequence, or the heavy chain or light chainsequence of MEDI0680.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810(Regeneron). In one embodiment, the anti-PD-1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of REGN2810.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591(Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprisesone or more of the CDR sequences (or collectively all of the CDRsequences), the heavy chain or light chain variable region sequence, orthe heavy chain or light chain sequence of PF-06801591.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 orBGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of BGB-A317 or BGB-108.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210(Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, theanti-PD-1 antibody molecule comprises one or more of the CDR sequences(or collectively all of the CDR sequences), the heavy chain or lightchain variable region sequence, or the heavy chain or light chainsequence of INCSHR1210.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro),also known as ANB011. In one embodiment, the anti-PD-1 antibody moleculecomprises one or more of the CDR sequences (or collectively all of theCDR sequences), the heavy chain or light chain variable region sequence,or the heavy chain or light chain sequence of TSR-042.

Further known anti-PD-1 antibodies include those described, e.g., in WO2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO2014/194302, WO 2014/209804, WO 2015/200119, U.S. Pat. Nos. 8,735,553,7,488,802, 8,927,697, 8,993,731, and 9,102,727, incorporated byreference in their entirety.

In one embodiment, the anti-PD-1 antibody is an antibody that competesfor binding with, and/or binds to the same epitope on PD-1 as, one ofthe anti-PD-1 antibodies described herein.

In one embodiment, the PD-1 inhibitor is a peptide that inhibits thePD-1 signaling pathway, e.g., as described in U.S. Pat. No. 8,907,053,incorporated by reference in its entirety. In one embodiment, the PD-1inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising anextracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to aconstant region (e.g., an Fc region of an immunoglobulin sequence). Inone embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune),e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated byreference in their entirety).

TABLE 4 Amino acid sequences of other exemplaryanti-PD-1 antibody molecules Nivolumab SEQ ID NO: 56 HCQVQLVESGGGVVQPGRSLRLDCKASGI TFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFL QMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKS LSLSLGKSEQ ID NO: 57 LC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRA TGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Pembrolizumab SEQ ID NO: 58 HCQVQLVQSGVEVKKPGASVKVSCKASG YTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTA YMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLA PCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVY TLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLGKSEQ ID NO: 59 LC EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLA SYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Pidilizumab SEQ ID NO: 60 HCQVQLVQSGSELKKPGASVKISCKASGY TFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTA YLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKSEQ ID NO: 61 LC EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLAS GVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Certain aspects and examples of combinations of the invention areprovided in the following listing of enumerated embodiments. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments of thepresent invention.

Embodiment 235. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition selected from any one of        Embodiments 1 to 83 or 161 to 164, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 236. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 237. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 238. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 239. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 240. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody selected from Table 2, and one or more pharmaceutically        acceptable excipients.

Embodiment 241. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients.

Embodiment 242. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody selected from Table 3, and one or more pharmaceutically        acceptable excipients.

Embodiment 243. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO: 37, and        one or more pharmaceutically acceptable excipients.

Embodiment 244. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 245. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 246. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 247. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody of Table 3.

Embodiment 248. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37.

Embodiment 249. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 250. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody of Table 2.

Embodiment 251. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17.

Embodiment 252. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, Tris buffer and mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 253. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, Tris buffer and sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 254. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 255. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 256. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 257. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 258. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 259. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 260. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 261. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 262. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 263. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor.

Embodiment 264. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 265. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 266. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 267. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 268. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 269. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 270. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 271. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 272. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 273. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 274. The pharmaceutical combination of any one of Embodiments264 to 273, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody ofTable 2.

Embodiment 275. The pharmaceutical combination of any one of Embodiments264 to 274, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:7 and a light chain variable domain comprising theamino acid sequence of SEQ ID NO:17.

Embodiment 276. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 277. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 278. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 279. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 280. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 281. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 282. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 283. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 284. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 285. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 286. The pharmaceutical combination of any one of Embodiments276 to 285, wherein the anti-PD-1 antibody is an anti-PD-1 antibody ofTable 3.

Embodiment 287. The pharmaceutical combination of any one of Embodiments276 to 286, wherein the anti-PD1 antibody is an anti-PD-1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:27 and a light chain variable domain comprisingthe amino acid sequence of SEQ ID NO:37.

Embodiment 288. The pharmaceutical combination of any one of Embodiments236 to 287, wherein the first pharmaceutical composition comprises atherapeutically effective amount of the compound of Formula A and thesecond pharmaceutical composition comprises a therapeutically effectiveamount of the immune checkpoint inhibitor, the anti-PD-L1 antibody orthe anti-PD-1 antibody.

Embodiment 289. The pharmaceutical combination of any one of Embodiments244 to 287, wherein the first pharmaceutical composition comprises atherapeutically effective amount of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, and the secondpharmaceutical composition comprises a therapeutically effective amountof the immune checkpoint inhibitor, the anti-PD-L1 antibody or theanti-PD-1 antibody.

Embodiment 290. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising tremelimumab        and one or more pharmaceutically acceptable excipients.

Embodiment 291. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lambrolizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 292. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising pidilizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 293. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising nivolumab and        one or more pharmaceutically acceptable excipients.

Embodiment 294. A combination of a pharmaceutical compositioncomprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lirilumab and        one or more pharmaceutically acceptable excipients.

Embodiment 295. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 296. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 297. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 298. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 299. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 300. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 301. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 302. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 303. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 304. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 305. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 306. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 307. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 308. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 309. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 310. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 311. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody of Table 3 and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 312. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 313. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients,    -   c) and a third pharmaceutical composition comprising nivolumab        and one or more pharmaceutically acceptable excipients.

Embodiment 314. A pharmaceutical combination comprising:

-   -   a) first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising lambrolizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 315. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, Tris buffer and mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 316. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, Tris buffer and sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 317. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 318. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 319. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 320. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 321. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 322. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 323. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 324. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 325. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 326. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 327. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 328. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 329. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 330. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 331. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 332. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 333. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 334. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 335. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 336. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 337. The pharmaceutical combination of any one of Embodiments355 to 364, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody ofTable 2.

Embodiment 338. The pharmaceutical combination of any one of Embodiments355 to 364, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:7 and a light chain variable domain comprising theamino acid sequence of SEQ ID NO:17.

Embodiment 339. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 340. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 341. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 342. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 343. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 344. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 345. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 346. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 347. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 348. A pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 349. The pharmaceutical combination of any one of Embodiments367 to 376, wherein the anti-PD-1 antibody is an anti-PD-1 antibody ofTable 3.

Embodiment 350. The pharmaceutical combination of any one of Embodiments367 to 376, wherein the anti-PD1 antibody is an anti-PD-1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:27 and a light chain variable domain comprisingthe amino acid sequence of SEQ ID NO:37.

Embodiment 351. The pharmaceutical combination of any one of Embodiments295 to 304, wherein the first pharmaceutical composition comprises atherapeutically effective amount of the compound of Formula A, thesecond pharmaceutical composition comprise a therapeutically effectiveamount of the immune checkpoint inhibitor, the anti-PD-L1 antibody, theanti-CTLA-4 antibody or the anti-PD-1 antibody, and the thirdpharmaceutical composition comprise a therapeutically effective amountof the immune checkpoint inhibitor, the anti-PD-L1 antibody, theanti-CTLA-4 antibody or the anti-PD-1 antibody.

Embodiment 352. The pharmaceutical combination of any one of Embodiments305 to 350, wherein the first pharmaceutical composition comprises atherapeutically effective amount of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, the secondpharmaceutical composition comprise a therapeutically effective amountof the immune checkpoint inhibitor, the anti-PD-L1 antibody, theanti-CTLA-4 antibody or the anti-PD-1 antibody, and the thirdpharmaceutical composition comprise a therapeutically effective amountof the immune checkpoint inhibitor, the anti-PD-L1 antibody, theanti-CTLA-4 antibody or the anti-PD-1 antibody.

The invention further provides a method for treating a solid tumor byadministering to a subject a pharmaceutical composition which comprisesa compound of Formula (A), or a pharmaceutically acceptable saltthereof, aluminum-containing particles, one or more pharmaceuticallyacceptable excipients and an immune checkpoint inhibitor.

The invention further provides a method for treating a solid tumor byadministering to a subject, either intratumorally, intramuscularly,intradermally or subcutaneously, a pharmaceutical composition whichcomprises a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, aluminum-containing particles, one or morepharmaceutically acceptable excipients and an immune checkpointinhibitor.

The invention further provides a method for treating a solid tumor byintratumorally administering to a subject a pharmaceutical compositionwhich comprises a compound of Formula (A), or a pharmaceuticallyacceptable salt thereof, aluminum-containing particles, one or morepharmaceutically acceptable excipients and an immune checkpointinhibitor.

The invention further provides a method for treating a solid tumor byadministering a pharmaceutical combination comprising:

-   -   a) a pharmaceutical composition comprising a compound of Formula        (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients, and    -   b) a pharmaceutical composition comprises an immune checkpoint        inhibitors and one or more pharmaceutically acceptable        excipients,    -   wherein the pharmaceutical compositions are administered        separately by the same or different routes of administration,        either concurrently or at different times. The pharmaceutical        composition comprising a compound of Formula (A), or a        pharmaceutically acceptable salt thereof, aluminum-containing        particles and one or more pharmaceutically acceptable excipients        may be adminstered either intratumorally, intramuscularly,        intradermally or subcutaneously, whereas the pharmaceutical        composition comprising the immune checkpoint inhibitors and one        or more pharmaceutically acceptable excipients may be        administered either intratumorally, intramuscularly,        intradermally, subcutaneously, intravenously, by intraperitoneal        injection, by lavage or by infusion.

In one embodiment is a method for treating a solid tumor byintratumorally administering a pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients and    -   b) a second pharmaceutical composition comprising one or more        immune checkpoint inhibitors and one or more pharmaceutically        acceptable excipients,    -   wherein both pharmaceutical compositions are intratumorally        administered into the same tumor or into the area immediately        surrounding the outer edge of the same tumor. In certain        embodiments these pharmaceutical compositions are administered        at different times, while in other embodiments these        pharmaceutical compositions are administered concurrently.

The invention further provide a method for treating a solid tumor byadministering a pharmaceutical combination comprising:

-   -   a) a first pharmaceutical composition comprises a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients,    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprises an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   wherein the pharmaceutical compositions are administered        separately by the same or different routes of administration,        either concurrently or at different times. The pharmaceutical        composition comprising a compound of Formula (A), or a        pharmaceutically acceptable salt thereof, aluminum-containing        particles and one or more pharmaceutically acceptable excipients        may be adminstered either intratumorally, intramuscularly,        intradermally or subcutaneously, whereas the pharmaceutical        compositions comprising an immune checkpoint inhibitor and one        or more pharmaceutically acceptable excipients may be        administered either intratumorally, intramuscularly,        intradermally, subcutaneously, intravenously, by intraperitoneal        injection, by lavage or by infusion.

In one embodiment is a method for treating a solid tumor byadministering a pharmaceutical combination:

-   -   a) a first pharmaceutical composition comprises a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients,    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprises an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   wherein the pharmaceutically compositions are intratumorally        administered into the same tumor or into the area immediately        surrounding the outer edge of the same tumor. In certain        embodiments, these three pharmaceutical compositions are        administered at different times, while in other embodiments        these three pharmaceutical compositions are administered        concurrently.

The invention further provides the use of a pharmaceutical compositionfor treating a solid tumor, wherein the pharmaceutical compositioncomprises a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, aluminum-containing particles, one or morepharmaceutically acceptable excipients and an immune checkpointinhibitor.

The invention further provides the use of a pharmaceutical combinationfor treating a solid tumor, wherein the pharmaceutical combinationcomprises

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

The invention further provides the use of a pharmaceutical combinationfor treating a solid tumor, wherein the pharmaceutical combinationcomprises

-   -   a) a first pharmaceutical composition comprises a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients,    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprises an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

The invention further provides a pharmaceutical composition for use intreating a solid tumor, wherein the pharmaceutical composition comprisesa compound of Formula (A), or a pharmaceutically acceptable saltthereof, aluminum-containing particles, one or more pharmaceuticallyacceptable excipients and an immune checkpoint inhibitor.

The invention further provides a pharmaceutical combination for use intreating a solid tumor, wherein the pharmaceutical combinationcomprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

The invention further provides a pharmaceutical combination for use intreating a solid tumor, wherein the pharmaceutical combination comprises

-   -   a) a first pharmaceutical composition comprises a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles and one or more pharmaceutically        acceptable excipients,    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprises an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

The solid tumors which may be treatable by such methods and usesinclude, but are not limited to, a breast cancer tumor, a bladder cancertumor, a head and neck cancer tumor, a non-small cell lung cancer tumor,a small cell lung cancer tumor, a colorectal cancer tumor, agastrointestinal stromal tumor, a gastroesophageal carcinoma, a renalcell cancer tumor, a prostate cancer tumor, a liver cancer tumor, acolon cancer tumor, a pancreatic cancer tumor, an ovarian cancer tumor,a lymphoma, a cutaneous T-cell lymphoma, or a melanoma.

Large solid tumors become infiltrated by a subpopulation of myeloidderived suppressor cells (mMDSC) that suppress anti-tumor immunity. Insome embodiments, the invention provides a method for treating an immunesuppressed tumor. An immune suppressed tumor is a tumor that containsimmune suppressive associated cells such as for example T Reg cells,myeloid derived suppressor cells (MDSC), M2 macrophages, and the like orimmune suppressive factors such as inducible nitric oxide synthase(iNOS), PD-L1, and the like.

The amount of a compound of Formula (A), or a pharmaceuticallyacceptable salt thereof, incorporated in a pharmaceutical composition ofthe invention, which is the used in a method or use of the invention,may vary according to factors known in art such as for example, thephysical and clinical status of the subject, the method ofadministration, the content of the formulation, the intended dosingregimen or sequence. In consideration of such factors the appropriateamount incorporated can be readily determined by one of ordinary skillin the art. By way of example, the pharmaceutical composition of theinvention may include an amount of a compound of Formula (A), or apharmaceutically acceptable salt thereof, to provide a dose of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,to a subject from about 0.05 mg to about 5 mg. Preferably thepharmaceutical composition of the invention includes an amount of acompound of Formula (A), or a pharmaceutically acceptable salt thereof,which provides a dose of a compound of Formula (A), or apharmaceutically acceptable salt thereof, to a subject from about 0.1 mgto about 1 mg.

While the disclosed methods and uses of such compositions andcombinations will typically be used to treat human subjects they mayalso be used to treat similar or identical diseases in othervertebrates, such as other primates, dogs, cats, horses, and cows.

Certain aspects and examples of the methods of the invention areprovided in the following listing of additional, enumerated embodiments.It will be recognized that features specified in each embodiment may becombined with other specified features to provide further embodiments ofthe present invention.

Embodiment 353. A method for treating a solid tumor by administering toa subject in need thereof a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an immune checkpoint inhibitor.

Embodiment 354. A method for treating a solid tumor by administering toa subject in need thereof a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an immune checkpoint inhibitor.

Embodiment 355. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an immune checkpoint inhibitor.

Embodiment 356. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an immune checkpoint inhibitor selected from a CTLA-4receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptorinhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIRreceptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor.

Embodiment 357. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and a PD-L₁ inhibitor.

Embodiment 358. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and a PD-1 receptor inhibitor.

Embodiment 359. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an anti-PD-L1 antibody.

Embodiment 360. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an anti-PD-L1 antibody of Table 2.

Embodiment 361. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an anti-PD-L1 antibody comprising a heavy chain variabledomain comprising the amino acid sequence of SEQ ID NO:7 and a lightchain variable domain comprising the amino acid sequence of SEQ IDNO:17.

Embodiment 362. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an anti-PD-1 antibody of Table 3.

Embodiment 363. A method for treating a solid tumor by intratumorallyadministering to a subject in need thereof a pharmaceutical compositioncomprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients and an anti-PD-1 antibody comprising a heavy chain variabledomain comprising the amino acid sequence of SEQ ID NO:27 and a lightchain variable domain comprising the amino acid sequence of SEQ IDNO:37.

Embodiment 364. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an immune checkpoint inhibitor for treating asolid tumor.

Embodiment 365. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an immune checkpoint inhibitor for treating asolid tumor.

Embodiment 366. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an immune checkpoint inhibitor for treating asolid tumor, wherein the checkpoint inhibitor is selected from a CTLA-4receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptorinhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIRreceptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor.

Embodiment 367. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and a PD-1 receptor inhibitor for treating a solidtumor.

Embodiment 368. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and a PD-L1 inhibitor for treating a solid tumor.

Embodiment 369. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody for treating a solidtumor.

Embodiment 370. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody of Table 2 for treatinga solid tumor.

Embodiment 371. Use of a pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:7 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:17 for treating a solid tumor.

Embodiment 372. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum-containingparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an immune checkpoint inhibitor for use intreating a solid tumor.

Embodiment 373. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an immune checkpoint inhibitor for use intreating a solid tumor.

Embodiment 374. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an immune checkpoint inhibitor for use intreating a solid tumor, wherein the checkpoint inhibitor is selectedfrom a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2 inhibitor.

Embodiment 375. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and a PD-1 receptor inhibitor for use in treating asolid tumor.

Embodiment 376. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and a PD-L1 inhibitor for use in treating a solidtumor.

Embodiment 377. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody for use in treating asolid tumor.

Embodiment 378. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody of Table 2 for use intreating a solid tumor.

Embodiment 379. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:7 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:17 for use in treating a solid tumor.

Embodiment 380. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-1 antibody of Table 3 for use intreating a solid tumor.

Embodiment 381. A pharmaceutical composition comprising3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, aluminum hydroxideparticles, a buffering agent, one or more pharmaceutically acceptableexcipients excipient and an anti-PD-L1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:27 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:37 for use in treating a solid tumor.

Embodiment 382. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination of any one of Embodiments 235to 294.

Embodiment 383. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination of any one of Embodiments 235to 294, wherein the first pharmaceutical composition is administeredintratumorally and the second pharmaceutical composition is administeredintratumorally, intramuscularly, intradermally, subcutaneously,intravenously, by intraperitoneal injection, by lavage or by infusion.

Embodiment 384. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

Embodiment 385. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

Embodiment 386. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients, and wherein the first pharmaceutical        composition is administered intratumorally and the second        pharmaceutical composition is administered intratumorally,        intramuscularly, intradermally, subcutaneously, intravenously,        by intraperitoneal injection, by lavage or by infusion.

Embodiment 387. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 388. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients,    -   wherein the checkpoint inhibitor is selected from a CTLA-4        receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 389. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-1        receptor inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 390. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 391. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 392. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 393. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-1        receptor inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 394. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-1        receptor inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 395. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 396. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 397. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 398. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2 and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 399. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17 and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 400. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 401. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody of Table 3 and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 402. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37 and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered by intraperitoneal injection.

Embodiment 403. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 404. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising tremelimumab        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 405. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lambrolizumab        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 406. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising pidilizumab        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 407. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising nivolumab and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 408. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lirilumab and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally and the second pharmaceutical composition is        administered intratumorally, intramuscularly, intradermally,        subcutaneously, intravenously, by intraperitoneal injection, by        lavage or by infusion.

Embodiment 409. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 410. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 411. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 412. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 413. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 414. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 415. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 416. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 417. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 418. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 419. The method of any one of Embodiments 409 to 418, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody of Table 2.

Embodiment 420. The method of any one of Embodiments 409 to 418, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:7and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO:17.

Embodiment 421. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 422. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 423. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 424. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 425. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 426. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 427. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 428. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 429. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 430. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 431. The method of any one of Embodiments 421 to 430, whereinthe anti-PD-1 antibody is an anti-PD-1 antibody of Table 3.

Embodiment 432. The method of any one of Embodiments 421 to 430, whereinthe anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:27 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:37.

Embodiment 433. The method of any one of Embodiments 409 to 432, whereinthe first pharmaceutical composition is administered intratumorally andthe second pharmaceutical composition is administered intratumorally,intramuscularly, intradermally, subcutaneously, intravenously, byintraperitoneal injection, by lavage or by infusion.

Embodiment 434. The method of any one of Embodiments 409 to 433, thefirst pharmaceutical composition is administered intratumorally and thesecond pharmaceutical composition is administered by intraperitonealinjection.

Embodiment 435. Use of a pharmaceutical combination of any one ofEmbodiments 235 to 294 for treating a solid tumor.

Embodiment 436. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

Embodiment 437. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

Embodiment 438. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 439. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-1        receptor inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 440. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 441. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 442. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2 and one or more pharmaceutically acceptable        excipients.

Embodiment 443. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17.

Embodiment 444. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 445. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody of Table 3 and one or more pharmaceutically acceptable        excipients.

Embodiment 446. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37.

Embodiment 447. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients.

Embodiment 448. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising tremelimumab        and one or more pharmaceutically acceptable excipients.

Embodiment 449. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lambrolizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 450. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising pidilizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 451. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising nivolumab and        one or more pharmaceutically acceptable excipients.

Embodiment 452. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lirilumab and        one or more pharmaceutically acceptable excipients.

Embodiment 453. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 454. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 455. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 456. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 457. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 458. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 459. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 460. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 461. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 462. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 463. The use of any one of Embodiments 453 to 462, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody of Table 2.

Embodiment 464. The use of any one of Embodiments 453 to 462, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:7and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO:17.

Embodiment 465. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 466. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 467. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 468. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 469. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 470. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 471. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 472. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 473. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 474. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 475. The use of any one of Embodiments 464 to 476, whereinthe anti-PD-1 antibody is an anti-PD-1 antibody of Table 3.

Embodiment 476. The use of any one of Embodiments 464 to 476, whereinthe anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:27 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:37.

Embodiment 477. A pharmaceutical combination of any one of Embodimentsfor Embodiments 235 to 294 for use in treating a solid tumor.

Embodiment 478. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

Embodiment 479. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients.

Embodiment 480. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitors and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 481. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising a PD-1        receptor inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 482. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprises a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 483. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 484. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2 and one or more pharmaceutically acceptable        excipients.

Embodiment 485. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17.

Embodiment 486. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 487. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody of Table 3 and one or more pharmaceutically acceptable        excipients.

Embodiment 488. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37.

Embodiment 489. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients.

Embodiment 490. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising tremelimumab        and one or more pharmaceutically acceptable excipients.

Embodiment 491. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lambrolizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 492. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising pidilizumab        and one or more pharmaceutically acceptable excipients.

Embodiment 493. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising nivolumab and        one or more pharmaceutically acceptable excipients.

Embodiment 494. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients, and    -   b) a second pharmaceutical composition comprising lirilumab and        one or more pharmaceutically acceptable excipients.

Embodiment 495. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 496. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 497. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 498. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 499. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 500. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 501. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 502. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 503. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 504. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody.

Embodiment 505. The pharmaceutical combination of any one of Embodiments495 to 504, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody ofTable 2.

Embodiment 506. The pharmaceutical combination of any one of Embodiments495 to 504, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:7 and a light chain variable domain comprising theamino acid sequence of SEQ ID NO:17.

Embodiment 507. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 508. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 509. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 510. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 511. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 512. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 513. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 514. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 515. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 516. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody.

Embodiment 517. The pharmaceutical combination of any one of Embodiments506 to 518, wherein the anti-PD-1 antibody is an anti-PD-1 antibody ofTable 3.

Embodiment 518. The pharmaceutical combination of any one of Embodiments506 to 518, wherein the anti-PD1 antibody is an anti-PD-1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:27 and a light chain variable domain comprisingthe amino acid sequence of SEQ ID NO:37.

Embodiment 519. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination of any one of Embodiments 295to 352.

Embodiment 520. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination of any one of Embodiments 295to 352, wherein the first pharmaceutical composition is administeredintratumorally, and the second pharmaceutical composition and the thirdpharmaceutical composition are administered intratumorally,intramuscularly, intradermally, subcutaneously, intravenously, byintraperitoneal injection, by lavage or by infusion.

Embodiment 521. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 522. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        first and the second pharmaceutical composition the third        pharmaceutical are then administered separately and sequentially        in any order.

Embodiment 523. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition comprising are administered simultaneously.

Embodiment 524. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 525. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        first and the second pharmaceutical composition and the third        pharmaceutical composition are then administered separately and        sequentially in any order.

Embodiment 526. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   d) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   e) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   f) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition are administered simultaneously.

Embodiment 527. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical, the second pharmaceutical        composition and the third pharmaceutical composition are        administered separately and sequentially in any order.

Embodiment 528. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        first and the second pharmaceutical composition and the third        pharmaceutical composition are then administered separately and        sequentially in any order.

Embodiment 529. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition comprising a different checkpoint inhibitor are        administered simultaneously.

Embodiment 530. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 531. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 532. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 533. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 534. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 535. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 536. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 537. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 538. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 539. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 540. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 541. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 542. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 543. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 544. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 545. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 546. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        first and the second pharmaceutical composition the third        pharmaceutical are then administered separately and sequentially        in any order.

Embodiment 547. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition comprising are administered simultaneously.

Embodiment 548. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 549. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        first and the second pharmaceutical composition and the third        pharmaceutical composition are then administered separately and        sequentially in any order.

Embodiment 550. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition are administered simultaneously.

Embodiment 551. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical, the second pharmaceutical        composition and the third pharmaceutical composition are        administered separately and sequentially in any order.

Embodiment 552. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        first and the second pharmaceutical composition and the third        pharmaceutical composition are then administered separately and        sequentially in any order.

Embodiment 553. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition, the second        pharmaceutical composition and the third pharmaceutical        composition comprising a different checkpoint inhibitor are        administered simultaneously.

Embodiment 554. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 555. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 556. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 557. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 558. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 559. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 560. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 561. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 562. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 563. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 564. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 565. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 566. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 567. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 568. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 569. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 570. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 571. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 572. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 573. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 574. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 575. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 576. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 577. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 578. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 579. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 580. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 581. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 582. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 583. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 584. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered        intratumorally, intramuscularly, intradermally, subcutaneously,        intravenously, by intraperitoneal injection, by lavage or by        infusion, and wherein the first pharmaceutical composition, the        second pharmaceutical composition and the third pharmaceutical        composition are administered separately and sequentially in any        order.

Embodiment 585. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally first, and the second pharmaceutical composition        and the third pharmaceutical composition are then administered        by intraperitoneal injection separately and sequentially in any        order.

Embodiment 586. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients,    -   and wherein the first pharmaceutical composition is administered        intratumorally, and the second pharmaceutical composition and        the third pharmaceutical composition are administered by        intraperitoneal injection, and wherein the first pharmaceutical        composition, the second pharmaceutical composition and the third        pharmaceutical composition are administered simultaneously.

Embodiment 587. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 588. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 589. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 590. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 591. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 592. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 593. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 594. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 595. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 596. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 597. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 598. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 599. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 600. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 601. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 602. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 603. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 604. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 605. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 606. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 607. The method of any one of Embodiments 587 to 606, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody of Table 2.

Embodiment 608. The method of any one of Embodiments 587 to 606, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:7and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO:17.

Embodiment 609. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 610. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 611. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 612. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 613. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 614. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 615. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 616. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 617. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 618. A method for treating a solid tumor in a subject byadministering a pharmaceutical combination, wherein the pharmaceuticalcombination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 619. The method of any one of Embodiments 609 to 618, whereinthe anti-PD-1 antibody is an anti-PD-1 antibody of Table 3.

Embodiment 620. The method of any one of Embodiments 609 to 618, whereinthe anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:27 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:37.

Embodiment 621. The method of any one of Embodiments 587 to 620, whereinthe first pharmaceutical composition is administered intratumorally, andthe second pharmaceutical composition and the third pharmaceuticalcomposition are administered intratumorally, intramuscularly,intradermally, subcutaneously, intravenously, by intraperitonealinjection, by lavage or by infusion.

Embodiment 622. The method of any one of Embodiments 587 to 620, thefirst pharmaceutical composition is administered intratumorally and thesecond pharmaceutical composition and third pharmaceutical compositionare administered by intraperitoneal injection.

Embodiment 623. Use of a pharmaceutical combination of any one ofEmbodiments 295 to 352 for treating a solid tumor.

Embodiment 624. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 625. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 626. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 627. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 628. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 629. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 630. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients.

Embodiment 631. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients.

Embodiment 632. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 633. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 634. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients.

Embodiment 635. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients.

Embodiment 636. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 637. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 638. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 639. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 640. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 641. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients.

Embodiment 642. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients.

Embodiment 643. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 644. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 645. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients.

Embodiment 646. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients.

Embodiment 647. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 648. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 649. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 650. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 651. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 652. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 653. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 654. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 655. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 656. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 657. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 658. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 659. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 660. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 661. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 662. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 663. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 664. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 665. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 666. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 667. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 668. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 669. The use of any one of Embodiments 649 to 668, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody of Table 2.

Embodiment 670. The use of any one of Embodiments 649 to 668, whereinthe anti-PD-L1 antibody is an anti-PD-L1 antibody comprising a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:7and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO:17.

Embodiment 671. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 672. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 673. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 674. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 675. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 676. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 677. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 678. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 679. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 680. Use of a pharmaceutical combination for treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 681. The use of any one of Embodiments 671 to 680, whereinthe anti-PD-1 antibody is an anti-PD-1 antibody of Table 3.

Embodiment 682. The use of any one of Embodiments 671 to 680, whereinthe anti-PD1 antibody is an anti-PD-1 antibody comprising a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO:27 and alight chain variable domain comprising the amino acid sequence of SEQ IDNO:37.

Embodiment 683. A pharmaceutical combination of any one of Embodiments295 to 352 for use in treating a solid tumor.

Embodiment 684. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 685. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 686. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 687. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 688. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 689. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 690. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients.

Embodiment 691. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients.

Embodiment 692. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 693. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 694. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients.

Embodiment 695. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients.

Embodiment 696. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof,        aluminum-containing particles, a buffering agent, and one or        more pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 697. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients.

Embodiment 698. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 699. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-L1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 700. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 701. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody of Table 2, and one or more pharmaceutically acceptable        excipients.

Embodiment 702. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:7 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:17, and        one or more pharmaceutically acceptable excipients.

Embodiment 703. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising a CTLA-4        receptor inhibitor and one or more pharmaceutically acceptable        excipients, and    -   c) a third pharmaceutical composition comprising a PD-1        inhibitor and one or more pharmaceutically acceptable        excipients.

Embodiment 704. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 705. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-1        antibody of Table 3, and one or more pharmaceutically acceptable        excipients.

Embodiment 706. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising an anti-CTLA-4        antibody and one or more pharmaceutically acceptable excipients,        and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody comprising a heavy chain variable domain comprising the        amino acid sequence of SEQ ID NO:27 and a light chain variable        domain comprising the amino acid sequence of SEQ ID NO:37, and        one or more pharmaceutically acceptable excipients.

Embodiment 707. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising a compound of        Formula (A), or a pharmaceutically acceptable salt thereof,        aluminum hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 708. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition comprising        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, aluminum        hydroxide particles, a buffering agent, and one or more        pharmaceutically acceptable excipients,    -   b) a second pharmaceutical composition comprising ipilimumab and        one or more pharmaceutically acceptable excipients, and    -   c) a third pharmaceutical composition comprising an anti-PD-L1        antibody and one or more pharmaceutically acceptable excipients.

Embodiment 709. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 710. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 711. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 712. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 713. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 714. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 715. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 716. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 717. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 718. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is selected from a        CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3        receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptor        inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a        PD-L2 inhibitor, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 719. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 720. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 721. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 722. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 723. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 724. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 725. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 726. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 727. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 728. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-L1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 729. The pharmaceutical combination of any one of Embodiments709 to 728, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibody ofTable 2.

Embodiment 730. The pharmaceutical combination of any one of Embodiments709 to 728, wherein the anti-PD-L1 antibody is an anti-PD-L1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:7 and a light chain variable domain comprising theamino acid sequence of SEQ ID NO:17.

Embodiment 731. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is        selected from a CTLA-4 receptor inhibitor, a PD-1 receptor        inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor,        a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1        inhibitor or a PD-L2 inhibitor.

Embodiment 732. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-100 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 733. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 734. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-50 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 735. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        mannitol, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 736. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 0.5 to 2 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 1 to 4 mg/mL, 5-20 mM Tris buffer and 5-10% (w/v)        sucrose, and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, which is different from the immune        checkpoint inhibitor in the second pharmaceutical composition,        and one or more pharmaceutically acceptable excipients, wherein        the checkpoint inhibitor is selected from a CTLA-4 receptor        inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor        inhibitor, TIM-3 receptor inhibitor, a BTLA receptor inhibitor,        a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2        inhibitor.

Embodiment 737. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 738. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 16 mM Tris buffer and 7.5% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 739. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) mannitol,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 740. A pharmaceutical combination for use in treating a solidtumor, wherein the pharmaceutical combination comprises:

-   -   a) a first pharmaceutical composition having a pH between 7.0        and 8.0 comprising 1 mg/mL of        3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic        acid, or a pharmaceutically acceptable salt thereof, a        suspension of aluminum hydroxide particles having an aluminum        content of 2 mg/mL, 5 mM Tris buffer and 8.25% (w/v) sucrose,        and    -   b) a second pharmaceutical composition comprising an immune        checkpoint inhibitor and one or more pharmaceutically acceptable        excipients, wherein the checkpoint inhibitor is an anti-PD-1        antibody, and    -   c) a third pharmaceutical composition comprising an immune        checkpoint inhibitor, and one or more pharmaceutically        acceptable excipients, wherein the checkpoint inhibitor is an        anti-CTLA-4 antibody.

Embodiment 741. The pharmaceutical combination of any one of Embodiments731 to 740, wherein the anti-PD-1 antibody is an anti-PD-1 antibody ofTable 3.

Embodiment 742. The pharmaceutical combination of any one of Embodiments731 to 740, wherein the anti-PD1 antibody is an anti-PD-1 antibodycomprising a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO:27 and a light chain variable domain comprisingthe amino acid sequence of SEQ ID NO:37.

Embodiment 743. The method of any one of Embodiments 165 to 189 orEmbodiments 353 to 363 or Embodiments 382 to 434 or Embodiments 519 to622, wherein the solid tumor is head and neck squamous cell carcinoma(HNSCC), melanoma or a visceral tumor.

Embodiment 744. The use of any one of Embodiments 190 to 211 orEmbodiments 364 to 371 or Embodiments 435 to 476 or of Embodiments 623to 682, wherein the solid tumor is head and neck squamous cell carcinoma(HNSCC), melanoma or a visceral tumor.

Embodiment 745. The pharmaceutical composition of any one of Embodiments212 to 234 or Embodiments 372 to 381, wherein the solid tumor is headand neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor.

Embodiment 746. The pharmaceutical combination of any one of Embodiments478 to 518 or Embodiments 683 to 742, wherein the solid tumor is headand neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor.

Embodiment 747. Use of a pharmaceutical composition of any one ofEmbodiments 1 to 4, Embodiments 10 to 83 or Embodiments 161 to 164, inthe manufacture of a medicament for treating a solid tumor.

Embodiment 748. The use of Embodiment 747, wherein the solid tumor ishead and neck squamous cell carcinoma (HNSCC), melanoma or a visceraltumor.

Embodiment 749. Use of a pharmaceutical combination of any one ofEmbodiments 235 to 352, in the manufacture of a medicament for treatinga solid tumor.

Embodiment 750. The use of Embodiment 749, wherein the solid tumor ishead and neck squamous cell carcinoma (HNSCC), melanoma or a visceraltumor.

The effect on tumor volume by administration of a compound of Formula(A), in the presence of aluminum-containing particles, with and withoutthe administration of one or more checkpoint inhibitors is shown inExample 14. It was found that the administration of a pharmaceuticalcomposition comprising a compound of Formula (A), or a pharmaceuticallyacceptable salt thereof, and aluminum-containing particles in was foundto be as effective in enhancing the immune response to a tumor whenadministered alone (not in combination), as that obtained with theadministration of a pharmaceutical composition comprising a compound ofFormula (A), or a pharmaceutically acceptable salt thereof, andaluminum-containing particles in in combination with the administrationof an immune checkpoint inhibitor. FIG. 9A shows the efficacy obtainedin the MC38 syngeneic colon cancer tumor model for a pharmaceuticalcomposition comprising Compound 15 and aluminum hydroxide administeredalone (not in combination), or administered in combination with theadministration of a pharmaceutical composition comprising either a CTLA4receptor inhibitor (anti-CTLA4 antibody) or an inhibitor of the PD-L1ligand (anti-PD-L1 antibody). It is also evident from FIG. 9A that theadministration of a pharmaceutical composition comprising Compound 15and aluminum hydroxide alone is more effective than the administrationof either the CTLA4 receptor inhibitor alone (not in combination) oradministration of the inhibitor of the PD-L1 ligand alone (not incombination).

In addition it was found that the immune response to a tumor was evenfurther enhanced by the administration of a pharmaceutical compositioncomprising a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, and aluminum-containing particles in combination with theadministration of two different checkpoint inhibitors. FIG. 9 furthershows the enhanced efficacy obtained using a triple combination of twodifferent checkpoint inhibitors and a pharmaceutical compositioncomprising a compound of Formula (A), or a pharmaceutically acceptablesalt thereof, and aluminum-containing particles. Specifically, FIG. 9Ashows efficacy obtained with the intratumor administration of apharmaceutical composition comprising Compound 15 and aluminum hydroxidein combination with the systemic administration (intraperitoneal) of aCTLA4 receptor inhibitor and the separate systemic administration(intraperitoneal) of a PD-L1 ligand inhibitor.

FIG. 9A is data obtained at the site of injection, whereas FIG. 9B showsthe data obtained at a distant location from the injection site. FIG. 9Bthe same behavior described above for FIG. 9A and demonstrates thatsystemic anti-tumor efficacy of a compound of Formula (A) adsorbed toaluminum hydroxide.

EXAMPLES

The compounds, pharmaceutical compositions comprising such compounds,pharmaceutical combinations comprising such compounds, methods of usingsuch pharmaceutical compositions and pharmaceutical combinations and useof such pharmaceutical compositions and pharmaceutical combinations ofthe present invention are shown in the following examples which areintended to illustrate the invention and are not to be construed asbeing limitations thereon.

Materials and Methods Compound 15/Alhydrogel® Suspensions

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. By way of example Table 5 lists the volume of a 20 mg/mLstock solution of compound 15 in 200 mM Tris (pH 7.4) buffer, the volumeof 2% Alhydrogel® and the volume of water used to make a final volume of10 mL with the desired concentrations of aluminum and compound 15 in 20mM Tris buffer.

TABLE 5 Com- Aluminum Aluminum Volume Volume pound 15 Final to Com-Compound 2% Water Final Conc Conc pound 15 15 stock Alhydrogel ® Volume(mg/mL) (mg/mL) ratio (mL) (mL) (mL) 0.25 0.013 0.05:1 0.125 0.013 9.860.25 0.025  0.1:1 0.125 0.025 9.85 0.25 0.063 0.25:1 0.125 0.063 9.810.25 0.125  0.5:1 0.125 0.125 9.75 0.25 0.250   1:1 0.125 0.250 9.630.25 0.375  1.5:1 0.125 0.375 9.50 0.25 0.500   2:1 0.125 0.500 9.380.30 0.015 0.05:1 0.150 0.015 9.84 0.30 0.030  0.1:1 0.150 0.030 9.820.30 0.075 0.25:1 0.150 0.075 9.78 0.30 0.150  0.5:1 0.150 0.150 9.700.30 0.300   1:1 0.150 0.300 9.55 0.30 0.450  1.5:1 0.150 0.450 9.400.30 0.600   2:1 0.150 0.600 9.25 0.50 0.025 0.05:1 0.250 0.025 9.730.50 0.050  0.1:1 0.250 0.050 9.70 0.50 0.125 0.25:1 0.250 0.125 9.630.50 0.250  0.5:1 0.250 0.250 9.50 0.50 0.500   1:1 0.250 0.500 9.250.50 0.750  1.5:1 0.250 0.750 9.00 0.50 1.000   2:1 0.250 1.000 8.751.00 0.050 0.05:1 0.500 0.050 9.45 1.00 0.100  0.1:1 0.500 0.100 9.401.00 0.250 0.25:1 0.500 0.250 9.25 1.00 0.500  0.5:1 0.500 0.500 9.001.00 1.000   1:1 0.500 1.000 8.50 1.00 1.500  1.5:1 0.500 1.500 8.001.00 2.000   2:1 0.500 2.000 7.50 2.00 0.100 0.05:1 1.000 0.100 8.902.00 0.200  0.1:1 1.000 0.200 8.80 2.00 0.500 0.25:1 1.000 0.500 8.502.00 1.000  0.5:1 1.000 1.000 8.00 2.00 2.000   1:1 1.000 2.000 7.002.00 3.000  1.5:1 1.000 3.000 6.00 2.00 4.000   2:1 1.000 4.000 5.003.00 0.150 0.05:1 1.500 0.150 8.35 3.00 0.300  0.1:1 1.500 0.300 8.203.00 0.750 0.25:1 1.500 0.750 7.75 3.00 1.500  0.5:1 1.500 1.500 7.003.00 3.000   1:1 1.500 3.000 5.50 3.00 4.500 1.5:1 1.500 4.500 4.00 3.006.000   2:1 1.500 6.000 2.50 5.00 0.250 0.05:1 2.500 0.250 7.25 5.000.500  0.1:1 2.500 0.500 7.00 5.00 1.250 0.25:1 2.500 1.250 6.25 5.002.500  0.5:1 2.500 2.500 5.00 5.00 5.000   1:1 2.500 5.000 2.50 5.007.500  1.5:1 2.500 7.500 0.00

In the preparation of the Compound 15/Alhydrogel® suspension used in theExamples herein, the stock suspension of Alhydrogel® was filtered bygravity filtration through a 100 μm cell strainer before mixing withstock solution comprising Compound 15. The resulting mixture/suspensionwas stirred for 5 minutes to allow Compound 15 to adsorb/bind to thealuminum of Alhydrogel®.

To determine the extent of Compound 15 binding to Alhydrogel® (i.e. %bound) in the Compound 15/Alhydrogel® suspension used in the Examplesherein, aliquots of the suspension were centrifuged to pellet the boundCompound 15/Alhydrogel® (e.g. 21,000×g for 10 min), and the amount offree Compound 15 in the supernatant was analyzed by HPLC/UV or LC/MS/MS.

Animals.

All animal related procedures were conducted in compliance with AnimalWelfare Act regulations and the Guide for the Care and Use of LaboratoryAnimals.

C57/BI6 mice were purchased from Jackson Laboratory, Bar Harbor, Maine,USA.

Male Wistar rats (weight range of 250-300 g) were purchased from Envigo,Indianapolis, IN USA.

Charles River Laboratories Balb/c female mice (age 6-8 weeks) werepurchased from Jackson Laboratory, Bar Harbor, Maine, USA

Cell Lines

MC38 and A20 cell line was purchased from ATCC (American Type CultureCollection, Manassas, VA).

Pharmacokinetic Regression Analysis

Pharmacokinetic parameters were calculated by non-compartmentalregression analysis using an in house fitting program. The highestplasma concentration of Compound 15 (Cmax) and the corresponding times(T_(max)) were recorded. The area under each concentration-time curve,AUC0-t or AUC0-∞ was calculated using the linear trapezoidal rule.Clearance (CL), the steady-state volume of distribution (Vss) and meanresidence time (MRT) of Compound 15 were calculated using the data fromthe intravenous dose and the following equations:

CL=Dose/AUC_(0-∞)

Vss=(Dose*AUMC_(0-∞))/(AUC_(0-∞))

MRT=(AUMC_(0-∞))/(AUMC_(0-∞))=Vss/CL

-   -   where AUC_(0-∞) and AUMC_(0-∞) are the area under the        concentration-time curve and area under the first moment        concentration-time curve from time 0 to infinity, respectively.

Bioavailability following subcutaneous injection of free or Alhydrogeladsorbed LHC165 was estimated as follows:

F=(AUMC_(0-∞,s.c.))/(AUMC_(0-∞,i.v.))*(Dose_(i.v.)/Dose_(s.c.))

Percent Treatment/Control (T/C)

Percent treatment/control (T/C) values for tumor were calculated usingthe following formula:

% T/C=100×ΔT/ΔC if ΔT>0

% Regression=100×ΔT/T _(initial) if ΔT<0

where:

-   -   T=mean tumor volume of the drug-treated group on the final day        of the study;    -   ΔT=mean tumor volume of the drug-treated group on the final day        of the study minus mean tumor volume of the drug-treated group        on initial day of dosing;    -   T_(initial)=mean tumor volume of the drug-treated group on        initial day of dosing;    -   C=mean tumor volume of the control group on the final day of the        study;    -   ΔC=mean tumor volume of the control group on the final day of        the study minus mean tumor volume of the control group on        initial day of dosing.

All data were expressed as mean±standard error of the mean (SEM). Deltatumor volume and body weight were used for statistical analysis. Betweengroups comparisons were carried out using a one-way ANOVA followed by apost hoc Tukey or Dunn's. For all statistical evaluations the level ofsignificance was set at p<0.05. Significance compared to the vehiclecontrol group is reported unless otherwise stated.

Example 1: Synthesis of Exemplary Compounds

Compound Nos. 1-28 of Table 1 were synthesized using the methodsdescribed in WO2011/049677.

Example 2: TLR7 Activation Assay

The EC₅₀ for TLR-7 stimulation by the exemplary compounds of Formula (A)are given in Table 6. Such EC₅₀ values were obtained using a reportergene assay wherein Human embryonic kidney 293 (HEK 293) cells werestably transfected with human TLR7 and an NF-kB-driven luciferasereporter vector (pNifty-Luciferase). As a control assay, normal Hek293transfected with pNifty-Luc were used. Cells were cultured in DMEMsupplemented with 2 mM L-glutamine, 10% heart inactivated FBS, 1%penicillin and streptomycin, 2 μg/ml puromycin (InvivoGen #ant-pr-5) and5 μg/ml of blasticidin (Invitrogen #46-1120). Bright-Glo™ Luciferaseassay buffer and substrate were supplied by Promega #E263B and #E264B(assay substrate and buffer respectively). 384 well clear-bottom plateswere supplied by Greiner bio-one (#789163-G) and were custom bar-codedplates. Cells were plated at 25,000 cells/well in 384-well plates in afinal volume of 50 μl of media. Cells were allowed to adhere to theplates after overnight (18 hours) culture at 37° C. and 5% CO₂. Seriallydiluted experimental and positive control compounds were then dispensedto each well and incubated for 7 hours at 37° C. and 5% CO₂. Cellsstimulated with DMSO alone also serve as negative controls. After theincubation, 30 μl of the pre-mix assay buffer and substrate buffer wereadded to each well according to manufacturer's instructions. Theluminescence signal was read on a CLIPR machine with an integration timeof 20 seconds per plate. Dose response curves are generated for eachcompound and EC₅₀ values were determined as the concentration that gives50% of the maximal signal. Such EC₅₀ values were obtained relative tothe activity of resiquimod set to 100%.

TABLE 6 Human TLR7 Compound EC₅₀ (nM) Number HEK293 1 1640 2 226 3 315 43170 5 559 6 308 7 1010 8 375 9 390 10 153 11 90 12 201 13 1051 14 88515 96 16 65 17 137 18 5 19 964 20 384 21 204 22 1160 23 791 24 4260 25975 26 2592 27 921 28 524

Example 3: Adsorption of Compounds of Formula (A) to Aluminum-ContainingParticles

By way of example, the percentage (%) of a compounds 6, 15, 17, 18 and20 to aluminum hydroxide in histidine buffer (pH 6.8) is given in Table7. The percentage (%) bound for compounds 6, 15, 17, 18 and 20 wasobtained as follows: to three volume equivalents of aqueous aluminumhydroxide (2 mg/mL) was added one volume equivalent of compound in 10 mMhistidine buffer (4 mg/mL) at pH 6.8. The resulting solution was diluted10-fold with blank histidine buffer to a final compound concentration of0.1 mg/mL. Diluted solutions were incubated at 37° C. for 5 hours. Thesamples were centrifuged at 14,000 rpm for 10 minutes to pellet theinsoluble. The supernatant (along with an internal standard) was thenevaluated by LC-MS/MS using a ballistic gradient (from 5% CH₃CN-0.5%formic acid to 95% CH₃CN-1.0% formic acid in 3.5 minutes) on a WatersAtlantis dC18 (50 mm×2.1 mm) column at room temperature against acalibration curve prepared at known compound concentrations ranging from0.005 to 50 μM. The concentration in the supernatant was calculated as %unbound to aluminum hydroxide compared to control; the % bound toaluminum hydroxide was calculated as 100% minus % unbound.

TABLE 7 Compound % Bound  1 98.2 15 96.0 17 94.5 18 96.2 20 97.0

Example 4: Binding Efficiency of Compounds of Formula (A) toAluminum-Containing Particles

The efficiency of binding of compounds of Formula (A) toaluminum-containing particles, as reflected in the percentage (%) boundto aluminum-containing particles, is a function of the (weight/weight)ratio of aluminum-containing particles to compound and to the finalconcentration (mg/mL) of compound in suspension with aluminum hydroxide.By way of example, the dependence of binding efficiency on thealuminum-containing particles to compound (w/w) ratio is shown in Table8, where the final concentration of Compound 15 is fixed at 2 mg/mL andthe amount of aluminum hydroxide is varied to obtain the desired ratio.The percentage of Compound 15 bound were obtained as described above inthe “Materials and Method”, and the suspensions of Compound15/Alhydroge® were prepared in 20 mM Tris buffer (pH 7.4) as describedabove in “Compound 15/Alhydrogel® Suspensions”.

TABLE 8 Com- Aluminum Aluminum pound 15 Final to Com- Com- Com- FinalConc Conc pound 15 pound 15 pound 15 (mg/mL) (mg/mL) ratio % Bound %Free 2 0.1 0.05:1 9.6 90.4 2 0.2  0.1:1 12.5 87.5 2 0.5 0.25:1 25.7 74.32 1  0.5:1 43.5 56.5 2 2   1:1 80.8 19.2 2 3  1.5:1 97.6 2.4 2 4   2:199.7 0.3

However, at a fixed aluminum hydroxide to Compound 15 ratio it wasobserved that the binding efficiency was also dependent on the finalconcentration of Compound 15 (see Table 9).

TABLE 9 Com- Aluminum Aluminum pound 15 Final to Com- Com- Com- FinalConc Conc pound 15 pound 15 pound 15 (mg/mL) (mg/mL) ratio % Bound %Free 0.25 0.625 2.5:1 90.7 9.3 0.25 5  20:1 97.6 1.4 1 2.5 2.5:1 93.56.5 3 7.5 2.5:1 97.1 2.9 3 5 1.7:1 99.6 0.4

Although, as seen in Table 10, % Bound levels >97% were obtained for lowfinal concentrations of Compound 15 by increasing the finalconcentration of aluminum. Sustained release of a Compound of Formula(A) was observed for % Bound >97, which allowed for control of thesystemic release of cytokines (see Example 5-9).

In addition, for (w/w) ratios of aluminum-containing particles tocompound of 1.5:1 and below, the binding efficiency has an apparent pHdependence. The effect of pH on binding efficiency is seen in Table 10,where the binding efficiency of Compound 15 at either a ratio ofaluminum hydroxide to Compound 15 (w/w) of 1.5:1 or 2:1 is given shown.The percentage of Compound bound was obtained as described above,although in Tris buffer at differing pH values. The suspensions ofCompound 15/Alhydroge® in Tris buffer at various were prepared asdescribed above in “Compound 15/Alhydrogel® Suspensions”.

TABLE 10 Aluminum hydroxide: Com- Compound 15 pound 15 Ratio (w/w) pH %Bound 1.5:1 7 98.5 1.5:1 7.5 85.9 1.5:1 8 91.1   2:1 7 99.3   2:1 7.599.7   2:1 8 99.1

Example 5: Injection Site Retention—MC38 Syngeneic Mouse Tumor Model OneWeek Study Mouse Pharmacokinetic Analysis of Free Compound 15 andCompound 15 Adsorbed to Alhydrogel®

A MC38 syngeneic mouse tumor model was used to investigate the systemicexposure of Compound 15 following:

-   -   a) a single intra-tumoral (i.t.) injection of 100 μg (˜4 mg/kg)        of free form Compound 15 in 20 mM Tris buffer pH 7.4,    -   b) a single intra-tumoral (i.t.) injection of Compound 15        adsorbed to Alhydrogel® suspension at a 1:1.5 ratio (w/w) of        Compound 15 to Alhydrogel®)-Suspension A described below and    -   c) a single subcutaneous (s.c.) injection of Compound 15        adsorbed to Alhydrogel® suspension at a 1:1.5 ratio (w/w) of        Compound 15 to Alhydrogel®-Suspension A described below.

Suspension A 2 mg/mL Compound 15, 3 mg/mL Aluminum Hydroxide and 7.5%(w/v) Sucrose in 16 mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:1.5Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 2.86 mg/mL of Compound 15, 12.5% (w/v)sucrose in 33.4 mM Tris (pH 7.4) buffer was prepared for dilution withthe 2% Alhydrogel® stock. The table below gives the volumes used to make5 mL of a suspension comprising 2 mg/mL Compound 15, 3 mg/mL Aluminumhydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) at a 1.5:1 ratioof Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume pound 15 Final to Com- Compound 2%Final Conc Conc pound 15 15 stock Alhydrogele ® (mg/mL) (mg/mL) ratio(mL) (mL) 2 3 1.5:1 3.5 1.5

MC38 Tumor Implantation in C57/BL6 Mice

MC38 cells were grown in sterile conditions in a 37° C. incubator with5% CO₂ for two weeks. The cells were cultured in DMEM media supplementedwith 10% FBS, cells were passed every 2-3 days. On the day of injection,cells were harvested (Passage 12) and re-suspended in HBSS at aconcentration of 2.5×10⁶/ml. Cells were Radil tested for mycoplasma andmurine viruses.

For each mouse, 0.25×10⁶ cells were implanted with subcutaneouslyinjection into right flank using a 28½ g needle (100 μL injectionvolume). Female C57BL/6 mice bearing the MC38 tumors were randomizedinto separate groups (n=3-24 mice per group) 10 days post tumor cellimplantation with an average tumor volume range of 95.05-194.36 mm³.

Dosing and Sampling in MC38 Tumor Bearing C57/BL6 Mice

Approximately 10 days after MC38 tumor implant, tumor bearing micereceived a single dose of vehicle, 100 μg of free Compound 15 solution(2 mg/mL) or Compound 15 adsorbed to Alhydrogel (1:1.5 w/w; 97% bound)by direct intra-tumoral (i.t.) injection or subcutaneous (s.c.)injection. The dose volume was 50 μL per animal. Plasma samples weretaken up to 7 days post dose at time points indicated in Table 11 (n=3animal per time point).

TABLE 11 Com- pound 15 Plasma Collection Dose (μg) Formulation Timespost dose (h) 100 (i.t) 20 mM Tris 0.083, 0.5, 1, 3, 6, 24 100 (i.t)Suspension 1, 6, 24, 48, 72, 96, A 120, 144, 168 100 (s.c) Suspension 1,6, 24, 48, 72, 96, A 120, 144, 168

Analysis of Mouse Plasma Samples by LC/MS/MS

Plasma concentrations of Compound 15 were quantified using a LiquidChromatography/Mass Spectrometry (LC/MS/MS) assay. Compound 20 (100ng/mL in water) was used as an internal standard. To 20 μL of eachplasma sample or appropriately diluted plasma sample, 25 μL of internalstandard solution was added, then mixed with 150 μL of extractionsolvent (methanol/acetonitrile, 80/20 by volume) to precipitate plasmaproteins. The samples were vortexed for 5 minutes then centrifuged withan Eppendorf Centrifuge 5810R (Eppendorf, Hamburg, Germany) at a settingof 4,000 rpm for 10 minutes at 4° C. Aliquot of supernatant (50 μL) wastransferred to a clean 96-well plate and mixed with 100 μL of Milli-Qwater. The mixed samples were injected (25 μL) onto a Waters XBridge C4analytical column (2.1×50 mm, 3.5 μm), and mobile phases consisted of0.1% formic acid in water (solvent A) and 0.1% formic acid inacetonitrile (solvent B). A gradient elution method at flow rate of 800μL/min was used from 20% B to 95% B in 1.5 min, held at 95% B until 2min, and return to initial condition with 20% B at 2.1 min, total runtime was 3 minutes.

The HPLC system, consisting of Agilent 1200 series binary pump (AgilentTechnologies Inc.), Agilent 1200 series micro vacuum degasser (AgilentTechnologies Inc.), CTC PAL-HTC autosampler (LEAP Technologies,Carborro, NC, USA) was interfaced to a AB Sciex API 4000 QTrap massspectrometer (AB Sciex LLC., Framingham, MA, USA). Mass spectralanalyses were carried out using electrospray ionization (ESI) in thepositive ion mode. Compound 15 (604.2>281.0) and internal standard(598.2>263.1) peak integration were performed using Analyst™ 1.4software. The lower limit of quantitation (LLOQ) in plasma was 0.25ng/mL. Known amounts of Compound 15 were spiked into plasma to createquality control samples with known concentrations of 4, 40, 200 and 1000ng/mL.

Plasma PK profiles of Compound 15 are shown in FIG. 1 and systemicexposures are summarized in Table 12. Direct intra-tumoral (i.t.)injection of 100 μg soluble or Alhydrogel® adsorbed Compound 15 in MC38tumor bearing mice gave very different PK profiles. Without theAlhydrogel®, soluble free Compound 15 was very quickly released intosystemic circulation and most drug eliminated by 24 h post i.t.injection with a half-life of 2.65 h. Alhydrogel® adsorbed Compound 15(or referred to Compound 15/Alhydrogel®) gave a controlled release PKprofile of Compound 15 as compared to soluble Compound 15. T_(max) wasdelayed, and C_(max) was dramatically reduced to 2-4% of that followingi.t. injection of soluble Compound 15.

The half-life of Compound 15 when adsorbed onto Alhydrogel® wassignificantly longer, and the slow release profile observed for Compound15 adsorbed onto Alhydrogel® demonstrates prolonged retention ofCompound 15 in the local tumor environment. In addition, subcutaneousinjection of Compound 15/Alhydrogel® gave a similar systemic PK profileas that following it. injection (FIG. 1 ), with similar C_(max), buthigher AUC. The AUC following a single s.c. or it. injection of 100 μgCompound 15/Alhydrogel® was ˜60% and 96% of that following i.t.injection of 100 μg soluble Compound 15, suggesting that the majority ofCompound 15 was desorbed from Alhydrogel® and cleared systemically after1 week following it. or s.c. injection.

TABLE 12 Compound 15 T_(1/2) T_(max) C_(max) AUC_((0−∞)) Dose (μg)Formulation (h) (h) (ng/mL) (ng*h/mL) 100 (i.t) 20 mM Tris 2.65 0.08310611 6219 100 (i.t) Suspension A 56.9 1-6 202 2762 100 (s.c) SuspensionA 29.4 1-6 191 6061 where: AUC(0-∞) is the area under the curve fromtime zero extrapolated to infinity; C_(max) is the maximum concentrationobserved; T_(max) is the time in which maximum concentration observed

Note: The pharmacokinetic properties of Compound 15 were examined infemale C57/BL6 mice following a single 2 mg/kg intravenous bolusadministration. The compound exhibited low plasma clearance of 18.1mL/min/kg, which is -20% of mouse liver blood flow (90 mL/min/kg, Daviesand Morris 1993). The mean volume of distribution at steady-state waslow (0.19 L/kg) as compared to total body water volume (0.725 L/kg,Davies and Morris 1993). Compound 15 had a short residence time (MRT) of0.17 h and elimination half-life of 1 h in mice.

Example 6: Injection Site Retention—MC38 Syngeneic Mouse Tumor Model TwoWeek Study

Mouse Pharmacokinetic analysis of Compound 15 adsorbed to Alhydrogel® Toevaluate systemic exposure of Compound 15 over an extended period oftime, a MC38 syngeneic mouse tumor model as described in Example 5 wasused, where the plasma concentration of Compound 15 was monitored for 2weeks following a single 50 μL intra-tumoral (i.t.) or subcutaneous(s.c.) 50 μL injection of Suspension B (described below) which delivered100 μg of Compound 15. Suspension B comprises a Compound 15/Alhydrogel®ratio of 1:2.

Suspension B 2 mg/mL Compound 15, 4 mg/mL Aluminum Hydroxide and 7.5%(w/v) Sucrose in 16 mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:2 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 3.34 mg/mL of Compound 15, 9.375% (w/v)sucrose in 20 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 1 mg/mL Compound 15, 2 mg/mL Aluminumhydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) at a 2:1 ratioof Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume pound 15 Final to Com- Compound 2%Final Conc Conc pound 15 15 stock Alhydrogele ® (mg/mL) (mg/mL) ratio(mL) (mL) 2 4 2:1 3 2

Plasma sample were obtained and analyzed as described in Example 5. TheCompound systemic PK profiles in MC38 tumor bearing mice were similar tothose shown in FIG. 1 , showing sustained release of Compound 15 intosystemic circulation from Compound 15/Alhydrogel® retained at localinjection sites. The the pharmacokinetic parameters (PK) are summarizedin Table 13.

TABLE 13 Compound 15 T_(max) C_(max) AUC_((0−∞)) Dose (μg) Formulation(h) (ng/mL) (ng*h/mL) 100 (i.t) Suspension B 1 343 8526 100 (s.c)Suspension B 6 388 9799 where: AUC(0-∞) is the area under the curve fromtime zero extrapolated to infinity; C_(max) is the maximum concentrationobserved; T_(max) is the time in which maximum concentration observed

The Compound 15/Alhydrogel® suspension provided a consistent, slow andsustained release of Compound 15 into systemic circulation, retainingCompound 15 at the local injection site for up to 2 week followingintratumoral (i.t.) injection and thereby prolonged and maximized localactivation, leading to enhanced anti-tumor efficacy. Systemic C_(max) ofCompound 15 was markedly reduced, and thereby minimizing cytokinesproduced systemically and potential cytokine related adverse effects(See Examples 7 and 8). Subcutaneous (s.c.) and intra-tumoral (i.t.)injections of Compound 15/Alhydrogel® suspension yielded similarsystemic PK profiles of Compound 15.

Example 7: Cytokine Profiles—MC38 Syngeneic Mouse Tumor Model One WeekStudy Mouse Pharmacodynamic Analysis of Free Compound 15 and Compound 15Adsorbed to Alhydrogel®

A MC38 syngeneic mouse tumor model (see Example 5) was used to obtainplasma cytokine profiles, including TNFa, IL-6 and IP-10 following:

-   -   a) a single 50 μL intra-tumoral (i.t.) injection of 100 μg (˜4        mg/kg) of free form Compound 15 in 20 mM Tris buffer pH 7.4,    -   b) a single 50 μL intra-tumoral (i.t.) injection of Compound 15        adsorbed to Alhydrogel® suspension at a 1:1.5 ratio (w/w) of        Compound 15 to Alhydrogel®)-Suspension A described above and    -   c) a single 50 μL subcutaneous (s.c.) injection of Compound 15        adsorbed to Alhydrogel® suspension at a 1:1.5 ratio (w/w) of        Compound 15 to Alhydrogel®-Suspension A described above.

The plasma samples obtained in Example 5 were analysed to obtain theplasma cytokine levels of Tumor necrosis factor alpha (TNFα),Interleukin 6 (IL-6) and Interferon gamma-induced protein 10 (IP-10).

Cytokine Measurements: IP-10 Levels Measured by ELISA

Plasma IP-10 (a proximal biomarker)_levels were measured using theQuantikine ELISA kit for mouse CxCL10/IP-10 (R&D Systems, Minneapolis,MN). Plasma samples were diluted 1:5 with calibrator diluent. 50 μLassay diluent/well was added to precoated plates followed by theaddition of standard, control or diluted samples/well. The plate wasincubated for 2 h at room temperature with shaking. After the 2 hincubation, the solution was decanted and wells washed 5 times with 400μL wash buffer. 100 μL of mouse IP-10 conjugate/well was added, and theplate was incubated for 2 h at room temperature with shaking. Thesolution was decanted and the wash step repeated as above. 100 μL ofsubstrate solution/well was added, and the plate was incubated for 30-45minutes at room temperature protected from light. Finally 100 μL of stopsolution/well was added followed by measurement of absorbance at 450 nmusing a SpectraMax Plus microplate reader (Molecular Devices). Lowerlimit of detection (LLOQ) for IP-10 from this measurement was 125 μg/mL,effective LLOQ for plasma unknown samples was 625 μg/mL due to 5 folddilution.

Plasma IP-10 levels were also measured using the Mouse IP-10 PlatinumELISA kit (eBioscience, San Diego, CA) according to manufacturer'sprotocol. Briefly, microwell strips were pre-coated with a polyclonalantibody to mouse IP-10 and washed 2 times with 400 μL wash buffer. 100μL of diluted plasma samples (1:10 dilution), standard (1:2 dilution)and blank/well was added, followed by 50 μL of Biotin conjugate/well.The plate was incubated on a microplate shaker set to 400 rpm for 2hours at room temperature. The supernatant was discarded and wells werewashed 6 times with 400 μL wash buffer. 100 μL/well of Streptavidin-HRPwas added, and plate was incubated with shaking for 1 hr at roomtemperature. The supernatant was discarded and washing step repeated asabove. 100 μL/well of TMB substrate solution was added and incubated atroom temperature for 10 minutes protected from light. The enzymereaction was stopped by the addition of 100 μL/well of stop solution,followed by measurement of absorbance at 450 nm using a SpectraMax Plusmicroplate reader (Molecular Devices). Lower limit of detection (LLOQ)for IP-10 from this measurement was 7.8 μg/mL, effective LLOQ for plasmaunknown samples was 78 μg/mL due to 10 fold dilution.

Cytokine Measurements: IL-6 and TNFα Levels

IL-6, TNFα and other cytokines were measured using the MultiPlex MouseProinflammatory Panel 1 ELISA kit (Meso Scale Discovery (MSD),Rockville, Maryland) according to manufacturer's protocol. Briefly, 50μL/well of prepared control or diluted plasma samples (1:2 with diluent41) was added onto a pre-coated plate with capture antibodies onindependent spots in each well. The plate was incubated for 2 h at roomtemperature with shaking, solution was decanted and the plate washed 3times with 200 μL of PBS/0.05% Tween 20. The detection antibodyconjugated with electrochemiluminescent labels (MSD SulfoTag) was thenadded (25 μL/well), and incubation was repeated as above. The detectionantibody solution was discarded and the wash step was repeated. Finally,150 μL of 2× Read Buffer T was added to each well, followed bymeasurement on a Sector Imager 6000 (Meso Scale Discovery). EffectiveLLOQ in plasma unknown samples was 0.3 μg/mL for TNFα, and 1.8-2.8 μg/mLfor IL-6.

Cytokine Release Profiles

Plasma samples from Example 5 were measured for several cytokine proteinconcentrations including IP-10 by ELISA assay, TNFα, IL-6 and othercytokines by Meso scale discovery multiplex assay (MSD).

Plasma samples were diluted 2 fold before cytokine measurements by MSDmultiplex assay, and TNFα, IL-6 profiles are shown in FIG. 2A and FIG.2B. Following both i.t. and s.c. injection of Compound 15/Alhydrogel®formulation in MC38 tumor bearing mice, the TNFα and IL-6 levelsincreased over pre-dose levels, where maximum induction occurred at ˜1 hpost injection, and the cytokine levels returned to baseline after 24 hpost dose. However, in mice with Compound 15/Alhydrogel® injectedintra-tumorally, both TNFα and IL-6 subsequently elevated above baselinefrom 96 h through 168 h post dose, while in s.c. injected mice, thecytokines remained at baseline.

Plasma IP-10 profiles are shown in FIG. 2C, maximum IP-10 inductionoccurred at 1-6 h post it. or s.c. injection of Compound 15/Alhydrogel®,similar to or slightly delayed with respect to T_(max) of Compound 15systemic concentration. IP-10 levels returned to baseline at 24-48 hpost dose, however in the i.t. dosed groups the IP-10 were elevatedagain from 72 h through 168 h. Overall the findings were similar tothose observed for TNFα and IL-6.

Example 8: Cytokine Profiles—MC38 Syngeneic Mouse Tumor Model Two WeekStudy Mouse Pharmacodynamic Analysis of Compound 15 Adsorbed toAlhydrogel®

To evaluate plasma cytokine profiles TNFa, IL-6 and IP-10 over anextended period of time, a MC38 syngeneic mouse tumor model as describedin Example 5 was used, where the TNFa, IL-6 and IP-10 levels weremonitored for 2 weeks following a single 50 μL intra-tumoral (i.t.) orsubcutaneous (s.c.) 50 μL injection of Suspension B (described above)which delivered 100 μg of Compound 15. Supension B comprises a Compound15/Alhydrogel® ratio of 1:2.

TNFa, IL-6 and IP-10 levels were obtained and analyzed as described inExample 5 and Example 7. The resulting profiles for TNFα and IL-6 areshown in FIG. 3A and FIG. 3B, where following both i.t. and s.c.injection of Compound 15/Alhydrogel® to MC38 tumor bearing mice, thelevels of TNFα and IL-6 increased over pre-dose levels, and maximuminduction occurred at ˜1 h post injection, with the cytokine levelsreturning to baseline after 24 h post dose. In mice with Compound15/Alhydrogel® injected intra-tumorally (i.t.), both TNFα and IL-6 levelsubsequently elevated above baseline from 96 h through 288 h post dose,while in s.c. injected mice, the cytokines remained at baseline after 24h. Intra-tumoral (i.t.) injection of a Alhydrogel® control did notinduce any cytokine level changes, suggesting the cytokine induction inCompound 15/Alhydrogel® treated groups was due to effect of Compound 15.Overall profiles were similar to those observed in the one-week study(Example 7). The plasma IP-10 levels are shown in FIG. 3C. Similar toTNFα and IL-6, plasma IP-10 levels were induced following i.t. and s.c.injection of Compound 15/Alhydrogel®.

Free soluble Compound 15 injected intra-tumorally (i.t.), was releasedquickly from the injection site with a Tmax ≤5 min, and at 24 h postinjection, essentially all of the injected Compound 15 was released andeliminated. However, when Compound 15 is adsorbed to Alhydrogel® thefast release rate of Compound 15 into the systemic circulation isminimized and a controlled release profile is observed, where Compound15 is slowly released over a period up to 2 weeks. Specifically, Cmaxwas reduced, and the half-life was extended, suggesting longer localretention of Compound 15/Alhydrogel® at the injection site, whichthereby minimized cytokines produced systemically and potential cytokinerelated adverse effects. Systemic cytokines, TNFα and IL-6, were inducedas a result of TLR7 pathways activation following i.t. and s.c.injections of Compound 15/Alhydrogel @ with maximum induction of thesecytokines occurring at 1˜-6 h post injection, similar to or slightlydelayed relative to Tmax of Compound 15 systemic PK. The early phase ofcytokine release may be attributed mostly to the initial compoundrelease into systemic circulation, however the second wave of cytokineinduction observed from 96 h up to 2 weeks following a single i.t.injection of Compound 15/Alhydrogel® (not observed in mice dosed withCompound 15/Alhydrogel® injected subcutaneously), may reflect targetrecruitment, activation and changes in local tumor environment.

Example 9: Injection Site Retention—Wistar Rat Dose Study Wistar RatPharmacokinetic Analysis of Free Compound 15 and Compound 15 Adsorbed toAluminum Hydroxide

The pharmacokinetic properties of Compound 15 were examined in naïvemale Wistar rats following:

-   -   a) a single 200 μL subcutaneous (s.c.) injection of 600 μg of        free form Compound 15 in 100 mM Tris buffer pH 7.4;    -   b) a single 200 μL subcutaneous (s.c.) injection of 50 μg of        Compound 15 adsorbed to aluminum hydroxide at a 1:2.5 ratio        (w/w) of Compound 15 to aluminum hydroxide-Suspension E        described below;    -   c) a single 200 μL subcutaneous (s.c.) injection of 200 μg of        Compound 15 adsorbed to aluminum hydroxide at a 1:2.5 ratio        (w/w) of Compound 15 to aluminum hydroxide-Suspension D        described below, and    -   d) a single 200 μL subcutaneous (s.c.) injection of 600 μg of        Compound 15 adsorbed to aluminum hydroxide at a 1:2.5 ratio        (w/w) of Compound 15 to aluminum hydroxide-Suspension C        described below.

Suspension C 3 mg/mL Compound 15, 7.5 mg/mL Aluminum Hydroxide 100 mMTris (pH 7.4)—Compound 15/Alhydrogel® (1:2.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 12 mg/mL of Compound 15 in 400 mMTris-HCl (pH 7.4) buffer was prepared, and mixed with 2% Alhydrogel®stock (10 mg/mL aluminum hydroxide) to obtain Suspension C.

The table below gives the volumes used to make 10 mL of Suspension Ccomprising 3 mg/mL Compound 15 and 7.5 mg/mL Aluminum hydroxide in 100mM Tris (pH 7.4) at a 2.5:1 ratio of Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume pound 15 Final to Com- Compound 2%Final Conc Conc pound 15 15 stock Alhydrogele ® (mg/mL) (mg/mL) ratio(mL) (mL) 3 7.5 2.5:1 2.5 7.5

Suspension D 1 mg/mL Compound 15, 2.5 mg/mL Aluminum Hydroxide 100 mMTris (pH 7.4)—Compound 15/Alhydrogel® (1:2.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 4 mg/mL of Compound 15 in 200 mMTris-HCl (pH 7.4) buffer was prepared, and mixed with 2% Alhydrogel®stock (10 mg/mL aluminum hydroxide) to obtain Suspension D.

The table below gives the volumes used to make 10 mL of Suspension Dcomprising 1 mg/mL Compound 15 and 2.5 mg/mL Aluminum hydroxide in 100mM Tris (pH 7.4) at a 2.5:1 ratio of Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume Volume pound 15 Final to Compound2% 100 mM Final Conc Conc Compound 15 stock Alhydrogel Tris (mg/mL)(mg/mL) 15 ratio (mL) (mL) (mL) 1 2.5 2.5:1 2.5 2.5 5

Suspension E 0.25 mg/mL Compound 15, 0.625 mg/mL Aluminum Hydroxide 100mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:2.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 1 mg/mL of Compound 15 in 125 mMTris-HCl (pH 7.4) buffer was prepared, and mixed with 2% Alhydrogel®stock (10 mg/mL aluminum hydroxide) to obtain Suspension E.

The table below gives the volumes used to make 10 mL of Suspension Ecomprising 0.25 mg/mL Compound 15 and 0.625 mg/mL Aluminum hydroxide in100 mM Tris (pH 7.4) at a 2.5:1 ratio of Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume Volume pound 15 Final to Com-Compound 2% 100 mM Final Conc Conc pound 15 stock Alhydrogel Tris(mg/mL) (mg/mL) 15 ratio (mL) (mL) (mL) 0.25 0.625 2.5:1 2.5 0.625 6.875

In this study, male Wistar rats (n=3 per group) were injectedsubcutaneously (s.c.) with 600 μg free Compound 15 or increasing dosesof 50, 200 and 600 μg of Compound 15 absorbed to aluminum hydroxide. Aninjection volume of 200 μL of Suspension E, Suspension D and SuspensionC was used to obtain 50, 200 and 600 μg of Compound 15 absorbed toaluminum hydroxide, respectively. The injection volume of 200 μL per ratwas not normalized to body weights of the rats. As described above theCompound 15/aluminum hydroxide ratio for Suspension E, Suspension D andSuspension C was fixed at 1:2.5 w/w.

Blood samples (˜100 μL each) were taken serially via saphenous bleedfrom each rat until 96 h post dose (see Table 9 for sampling schedule).Blood samples were centrifuged to separate plasma and the plasma sampleswere frozen at −20° C. prior to analysis using LC/MS/MS (as described inExample 5) to obtain the systemic concentrations of Compound 15.

In addition, plasma samples were analyzed for Interferon gamma-inducedprotein 10 (IP-10) levels as described in Example 7.

Plasma PK profiles of Compound 15 are shown in FIG. 4 and systemicexposures are summarized in Table 14.

TABLE 14 Compound 15 % Free T_(1/2) T_(max) C_(max) AUC_((0-∞)) Dose(μg) Formulation Compound 15 (h) (h) (ng/mL) (ng*h/mL) 50 (s.c)Suspension E 9.3 2.2 0.38 45 188 200 (s.c) Suspension D 6.5 10.5 1.00114 937 600 (s.c) Suspension C 2.9 21.1 0.83 185 2236 600 (s.c) 100 mMTris 100 2.1 0.25 3655 2560 where: AUC(0-∞) is the area under the curvefrom time zero extrapolated to infinity; C_(max) is the maximumconcentration observed; T_(max) is the time in which maximumconcentration observed.

The adsorption efficiency appeared to decrease at lower concentrationsof Compound 15 (at a fixed Compound 15/aluminum hydroxide ratio),resulting in a higher percent of free Compound 15 and consequently anincrease in systemic IP-10 (see below).

The total AUC approximately increased proportionally with the dose of asingle subcutaneous injection of 50 to 600 μg of Compound 15 adsorbed toaluminum hydroxide, whereas Cmax increased less proportionally with doselevel, likely due to the higher percent of free Compound 15 at lowerdose and the resulting shorter half-lives at lower doses.

FIG. 4 shows that at the 600 μg dose level, free Compound 15 in 100 mMTris buffer exhibited rapid release of Compound 15 into systemiccirculation following subcutaneous injection (plasma concentration of3655 ng/mL at first sampling time point of 0.25 h), whereas whenCompound 15 was adsorbed onto aluminum hydroxide a sustained slowrelease profile was obtained. Also, in comparison to free Compound 15,Cmax was reduced, and half-life extended for Compound 15 adsorbed ontoaluminum hydroxide.

Note: The pharmacokinetic properties of Compound 15 in 50 mM Tris/0.9%NaCl (pH 7.4) were examined in male Wistar rats following a single 1mg/kg intravenous bolus administration. The compound exhibited lowplasma clearance of 9.2 mL/min/kg, which is -17% of rat liver plasmaflow (55 mL/min/kg, Davies and Morris 1993). The mean volume ofdistribution at steady-state was low (0.11 L/kg) as compared toextracellular fluid volume (0.3 L/kg, Davies and Morris 1993). As aresult, the compound exhibited a short residence time (MRT) of 0.2 h andterminal half-life of 1.2 h.

Example 10: Injection Site Retention—Wistar Rat Study Wistar RatPharmacokinetic Analysis of Free Compound 15 and Compound 15 Adsorbed toAluminum Hydroxide

The pharmacokinetic properties of Compound 15 were examined in naïvemale Wistar rats following:

-   -   a) a single 200 μL subcutaneous (s.c.) injection of 600 μg of        free form Compound 15 in 100 mM Tris buffer pH 7.4;    -   b) a single 200 μL subcutaneous (s.c.) injection of 50 μg of        Compound 15 adsorbed to aluminum hydroxide at a 1:20 ratio (w/w)        of Compound 15 to aluminum hydroxide-Suspension G described        below; and    -   c) a single 200 μL subcutaneous (s.c.) injection of 600 μg of        Compound 15 adsorbed to aluminum hydroxide at a 1:1.7 ratio        (w/w) of Compound 15 to aluminum hydroxide-Suspension F        described below.

Suspension F 3 mg/mL Compound 15, 5 mg/mL Aluminum Hydroxide 100 mM Tris(pH 7.4)—Compound 15/Alhydrogel® (1:1.7 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 12 mg/mL of Compound 15 in 300 mMTris-HCl (pH 7.4) buffer was prepared, and mixed with 2% Alhydrogel®stock (10 mg/mL aluminum hydroxide) to obtain Suspension F.

The table below gives the volumes used to make 10 mL of Suspension Fcomprising 3 mg/mL Compound 15 and 5 mg/mL Aluminum hydroxide in 100 mMTris (pH 7.4) at a 1.7:1 ratio of Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume Volume pound 15 Final to Com-Compound 2% 100 mM Final Conc Conc pound 15 stock Alhydrogel Tris(mg/mL) (mg/mL) 15 ratio (mL) (mL) (mL) 3 5 1.7:1 2.5 5 2.5

Suspension G 0.25 mg/mL Compound 15, 5 mg/mL Aluminum Hydroxide 100 mMTris (pH 7.4)—Compound 15/Alhydrogel® (1:20 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 1 mg/mL of Compound 15 in 200 mMTris-HCl (pH 7.4) buffer was prepared, and mixed with 2% Alhydrogel®stock (10 mg/mL aluminum hydroxide) to obtain Suspension G.

The table below gives the volumes used to make 10 mL of Suspension Gcomprising 0.25 mg/mL Compound 15 and 5 mg/mL Aluminum hydroxide in 100mM Tris (pH 7.4) at a 20:1 ratio of Alhydrogel® to Compound 15.

Com- Aluminum Aluminum Volume Volume Volume pound 15 Final to Com-Compound 2% 100 mM Final Conc Conc pound 15 stock Alhydrogel Tris(mg/mL) (mg/mL) 15 ratio (mL) (mL) (mL) 0.25 5 20:1 2.5 5 2.5

The systemic concentration of Compound 15 was evaluated following asingle 200 μL subcutaneous injection of two different dose levels ofCompound 15 adsorbed to aluminum hydroxide, where the aluminum hydroxidewas at a fixed dose concentration of 5 mg/mL.

In this study, two groups male Wistar rats (n=3 per group) were injectedsubcutaneously (s.c.) with either 50 μg or 600 μg of Compound 15absorbed to aluminum hydroxide. An injection volume of 200 μL ofSuspension G and Suspension F was used to obtain 50 and 600 μg ofCompound 15 absorbed to aluminum hydroxide, respectively. The injectionvolume of 200 μL per rat was not normalized to body weights of the rats.As described above the Compound 15/aluminum hydroxide ratio forSuspension F was 1:1.7 w/w, while for Suspension G it was 1:20 w/w.

Blood samples (˜100 μL each) were taken serially via saphenous bleedfrom each rat until 168 h post dose (see Table 9 for sampling schedule).Blood samples were centrifuged to separate plasma and the plasma sampleswere frozen at −20° C. prior to analysis using LC/MS/MS (as described inExample 5) to obtain the systemic concentrations of Compound 15.

In addition, plasma samples were analyzed for Interferon gamma-inducedprotein 10 (IP-10) levels as described in Example 7.

In this study, two formulations with a fixed aluminum hydroxideconcentration (5 mg/mL) but differing concentrations of Compound 15(i.e. two different Compound 15 to aluminum hydroxide ratios) were usedto evaluate the binding efficiency on the systemic exposure of Compound15. Systemic exposures of Compound 15 following a single s.c. injectionof 50 and 600 μg of Compound 15/aluminum hydroxide are summarized inTable 15, and PK profiles are illustrated in FIG. 5A. The data obtainedin Example 9 for free Compound 15 in 100 mM Tris buffer is alsoincluded.

TABLE 15 Compound 15 % Free T_(1/2) T_(max) C_(max) AUC_((0-∞)) Dose(μg) Formulation Compound 15 (h) (h) (ng/mL) (ng*h/mL) 50 (s.c)Suspension G 1.4 12.3 7 7 164 600 (s.c) Suspension F 0.4 37.3 7 48 2053600 (s.c) 100 mM Tris 100 2.1 0.25 3655 2560 where: AUC(0-∞) is the areaunder the curve from time zero extrapolated to infinity; C_(max) is themaximum concentration observed; T_(max) is the time in which maximumconcentration observed.

As seen in Table 15, the two formulations resulted in high adsorption ofCompound 15 to aluminum hydroxide (>98%). When the PK data obtained fromExample 9 and Example 10 are compared, it is evident that the AUC forboth 50 and 600 μg dose levels are similar, whereas the Tmax is delayedand the Cmax values are further reduced in Example 10.

FIG. 5A shows the systemic PK profiles of Compound 15 obtained from thedifferent doses and shows that adsorption of Compound 15 onto aluminumhydroxide resulted in a consistent, slow and sustained release ofCompound 15 into systemic circulation and retained Compound 15 at thelocal injection site for up to 1 week following subcutaneous injection.

FIG. 5B show the plasma IP-10 profiles in male Wistar rats following asingle subcutaneous injection of free Compound 15 or Compound 15adsorbed onto aluminum hydroxide at 50 and 600 μg dose levels. The PDresponse as measured by IP-10 induction was delayed relative to plasmaTmax, and maximum IP-10 levels were between 7 to 24 h post s.c.injection of 50 and 600 μg Compound 15/aluminum hydroxide. Whereas, andthe maximum IP-response occurred around 3 h post s.c. injection of 600μg free Compound 15. Also, in comparison to the results obtained for 600μg Compound 15/aluminum hydroxide, the results obtained for 600 μg freeCompound 15 showed higher peak IP-10 levels with a fast rate of decline,which is consistent with respective PK profiles.

Example 11: Systemic Exposure to Aluminum

ICP-MS was used to analyze of the serum aluminum levels afteradministration of Compound 15 with aluminum hydroxide and afteradministration of aluminum hydroxide alone.

Whole blood samples were collected into a serum-separator tube (CovidienMonoject™ Royal Blue Stopper trace element blood collection tube, Code8881307006). After collection, the tube was gently inverted 5 times tomix clot activator with blood and allow clotting for at least 30 minutesin a vertical position but maximum 60 minutes at room temperature. Aclot must be visually confirmed before centrifugation. All bloodspecimens were centrifuged at approximately 1500 to 2200×g force forapproximately 10 minutes at room temperature. The resultant serum waspoured/transferred (using metal free tips-Thomas Brand pipettetips/transfer tips) into uniquely labeled metal free tubes (Sorenson™multi safeseal microcentrifuge tubes) and frozen as soon as practicalover dry ice before being transferred into a freezer set to maintain at−80° C.

Metal free/trace metal grade containers/tubes/tips (<1 ng/g Al) wereused for sample handling and samples were transferred by pouring orusing metal free tips. The specimen handling area was kept clean andfree of dust and the venipuncture site were cleaned with alcohol. Noiodone containing products were used, including povidone-iodine swabs orpads. Serum samples were not reamed with a wooden stick to remove clotsand specimen were not reamed with a wooden stick to assist serumtransfer.

All containers, tubes and pipette tips were soaked in 10% TraceMetalGrade Nitric acid overnight and then soaked in purified water for atleast 12 hours. This was followed by rinse with purified water for atleast three times before use.

Study animals were divided in five groups, receiving 2 mL/animal ofbuffer without aluminum hydroxide (group 1) or 2 mL/animal of buffercontaining aluminum hydroxide formulated with Compound 15 at 0 mg/animal(group 2), 0.3 mg/animal (group 3), 1 mg/animal (group 4) and 2mg/animal (group 5). The buffer used was 16 mM Tris, 7.5% (w/v) sucrose,pH 7.5 and for groups 2-5 the aluminum hydroxide was present at 2 mg/mL.

Groups 1, 2, and 5 consisted of five animals/sex/group; two of whichwere designated for recovery. Groups 3 and 4 consisted of threeanimals/sex/group. Blood samples were collected from all animals on Day1 pre-dose and at approximately 0.5, 3, 6, 24, 72, and 168 hours postdose. Blood samples were collected from all main and recovery studyanimals on Day 29 at approximately 0.5, 3, 6, and 24 hours post dose.Blood samples were also collected from recovery animals (Groups 1, 2,and 5) on Day 29 at 72 hours post dose, and on Days 36, 43, 50, 57, and63.

For ICP-MS analysis, 50 μL of sample (surrogate matrix (for double blankand blank), calibration standards (10 to 1000 ng/mL), QC samples (30,300 and 750 ng/mL), and study samples) was added into assigned 1.5-mLmetal free plastic centrifuge tube pre-washed using acid as above. A 20μL aliquot of the internal standard working solution (50 ng/mL) and a500 μL aliquot of 0.1% HNO3 were added to all tubes. This was followedby vortex-mixing for about 3 minutes and centrifugation at 12,000 rpmfor 5 min. A 500 μL volume of the supernatant from each tube wastransferred into assigned plastic sample tube pre-washed using the acidas above. All tubes were placed in the auto-sampler according to thepre-arranged assay sequence.

Aluminium at m/z 27 and Rhodium at m/z 103 were measured using anAgilent 7700x ICP-MS instrument (Agilent Technologies UK Ltd) equippedwith an Agilent ASX-500 autosampler. The Agilent MassHunter (versionC.01.02) software was used for data collection and integration WatsonLIMS Version 7.3 was used for the sample management, data management,and calculation of the sample concentrations. (Thermo Fisher Scientific,USA).

Instrument Auto Tune and Tune Check.

Tuning solution that contains 1 ng/mL of Ce, Co, Li, Mg, TI, and Y in 2%HNO3 (Agilent part #5188-6564 or equivalent) was used for autotune andtune check. Auto tune was performed when the ICP was ignited. A TuneCheck was set at the beginning of a batch analysis. If the Tune Checkresults failed to meet the criteria determined, the batch was stoppedautomatically.

Autosampler and Operation Conditions:

Autosampler Needle rinse  8 sec, pump speed 0.5 rps Purified water Wash1 120 sec, pump speed 0.4 rps   2% HNO₃/H₂O (v/v) Wash 2  60 sec, pumpspeed 0.3 rps 0.1% HNO₃/H₂O (v/v) Sample introduction 20 sec, pump speed0.4 rpm Stabilize 20 sec, pump speed 0.1 rps

ICP Mass Spectrometer Agilent 7700x Nebulizer Concentric MicroMistnebulizer Spray chamber temp 2° C. Operation mode He Tuning parameters*Serum RF power (W) 1550 RF matching (V) 1.8 Sampling depth (mm) 8.0Carrier gas (L/min) 1.00 Nebulizer pump (rps) 0.10 Make up gas (L/min)0.10 Lenses Extract 1 −5.8 Extract 2 −185 Omega bias −90 Omega Lens 7.4Cell entrance −112 Cell exit −109 Deflect 8.2 Plate bias −104 Cell Gas(helium, mL/min) 4.5 OctP bias −18.2 OctP RF 200 Energy discrimination4.0 Integration peak Aluminum 0.099 sec pattern: 3 points Rhodium ISTD0.099 sec Replicates: 3

Results

No quantifiable aluminum concentrations were observed in the serumsamples collected from the control group animals (group 1) administeredwithout aluminum hydroxide and Compound 15.

FIG. 6 shows the serum aluminum concentrations vs time post dose forGroup 2 (aluminum hydroxide (2 mL/animal) Al(OH)₃ in 16 mM Tris, 7.5%(w/v) sucrose, pH 7.5, (0 mg/animal of Compound 15)) and Group 5(aluminum hydroxide (2 mL/animal) Al(OH)₃ in 16 mM Tris, 7.5% (w/v)sucrose, pH 7.5, (2 mg/animal of Compound 15)). In FIG. 3 a differencein the serum aluminum concentration between Group 2 (no Compound 15) andGroup 5 (2 mg/animal of Compound 15) is seen which indicates thatsystemic exposure to aluminum after administration of Compound 15 boundto aluminum hydroxide was significantly lower than systemic exposureafter administration of aluminum hydroxide alone.

Example 12: Serum and Urine Exposure to Aluminum

The pharmacokinetics and mass balance of aluminum and Compound 15 wereinvestigated following a single subcutaneous (s.c.) dose (1 mL) ofSuspension H (Compound 15/Alhydrogel® at a 2:1 ratio of aluminum toCompound 15) in male Wistar rats. In addition, the pharmacokinetics ofaluminum were investigated following a single intravenous (i.v.) dose(0.5 mL) of 0.4 mg/mL AlCl₃·6H₂O (equivalent to 0.2 mg of aluminum) inmale Wistar rat. Additionally, a control group dosed subcutaneously withsaline were evaluated for environmental background aluminum levels.

Suspension H 1 mg/mL Compound 15, 2 mg/mL Aluminum Hydroxide and 5.5%(w/v) Mannitol in 5 mM Tris (pH 7.5)—Compound 15/Alhydrogel® (1:2 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 1.25 mg/mL of Compound 15, 6.875% (w/v)mannitol in 6.25 mM Tris (pH 7.5) buffer was prepared for dilution withthe 2% Alhydrogel® stock. The table below gives the volumes used to make5 mL of a suspension comprising 1 mg/mL Compound 15, 2 mg/mL Aluminumhydroxide and 5.5% (w/v) mannitol in 5 mM Tris (pH 7.5) at a 2:1 ratioof Alhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% FinalConc Final Conc pound 15 stock Alhydrogel ® (mg/mL) (mg/mL) 15 ratio(mL) (mL) 1 2 2:1 4 1Serum and Urine Sample Collection & Handling: i.v. And s.c. Groups

Metal free/trace metal grade containers/tubes/tips (<1 ng/g Al) wereused for sample handling. Aluminum content was analyzed in serum andurine (Frontage Laboratories).

Approximately 0.3 to 0.5 mL of blood samples were collected from carotidartery cannulation at 0 (pre dose), 0.083 (IV only), 0.25 (IV only),0.5, 3, 6, 24, 72, 168, 336, 504, 672 hours post dose.

Urine was collected from each animal for the following periods: 0 (24 hbefore dose), 0-24, 24-48, 48-72, 72-96, 96-168 hours post dose, thenweekly up to 672 h. The urine samples were stored at −20° C. untilanalyzed. Feces were collected from each animal and samples were pooledper subject at the end of study at 672 h.

Compound 15 and aluminum levels were analyzed in the serum and urinesamples obtained from the s.c. group whereas only aluminum levels wereanalyzed in the i.v. group.

Serum and Urine Sample Collection & Handling: Control Groups

Approximately 0.3 to 0.5 mL of blood samples were collected by carotidartery cannulation at 0 (pre dose), 0.5, 3, 24, 168, 336, 504, 672 hourspost dose. Blood samples sat at room temperature for at least 20 minbefore centrifuging to obtain the serum. Serum samples were transferredto another tube and stored at −70° C. until analyzed.

Urine was collected from each animal for the following periods: 0 (24 hbefore dose), 0-24, 48-72, 96-168 hours post dose, then weekly up to 672h. The urine samples were stored at −20° C. until analyzed. Feces werecollected from each animal and samples were pooled per subject at theend of study at 672 h. The feces samples were stored at −20° C.

FIG. 7 shows the aluminum serum concentration vs. time profile aftersubcutaneous administration of Suspension H and intravenousadministration of AlCl₃-6H₂O in saline.

The aluminum pharmacokinetics parameters obtained after a singlesubcutaneous dose of Compound 15/Alhydrogel® (equivalent to 2 mg ofaluminum per animal) show low systemic exposure, with a mean C_(max) ofaluminum in serum of 76.2 ng/mL and a mean T_(max) at 3.2 hours postdose. The AUC_(last) and AUC_(inf) were 3950 ng·h/mL and 4490 ng/mL,respectively. The elimination half-life was 23.8 hours. Thebioavailability was low (0.6%).

The aluminum pharmacokinetics parameters obtained after a singleintravenous dose of AlCl₃·6H₂O (equivalent to 0.2 mg of aluminum peranimal) gave a mean C_(max) of aluminum in serum of 26000 ng/mL and amean T_(max) at 0.22 hours post dose. The AUC_(last) and AUCinf were67400 ng·h/mL and 67500 ng/mL, respectively. The elimination half-lifewas 3.40 hours. The CL was 0.71 mL/h, mainly via renal excretion basedon mass balance data. The Vss was moderate at 7.66 mL, based on totalbody water of 7.8 mL in rat (Davies B and Morris T (1993) Physiologicalparameters in laboratory animals and humans, Pharmaceutical Research.Vol. 10, pp 1093-95).

Following a single intravenous dose of AlCl₃·6H₂O, urine was the onlyexcreta analyzed and the mean recovery of aluminum in urine was nearcomplete at ˜0.2 mg, suggesting renal excretion was the main clearancepathway. For the mass balance after a single subcutaneous dose ofCompound 15/Alhydrogel® the majority of the aluminum was found at thesite of injection (71.7% to 85.7%), with ˜1% and ˜2% of aluminumrecovered in urine and feces, respectively. There were trace amounts ofaluminum (<0.01%) found in bone, brain, kidney and liver.

Based on the control group, the background environmental exposure ofaluminum in urine and serum was ˜10 ng/mL.

Taken together, the aluminum pharmacokinetic parameters obtained showthat the systemic levels of aluminum are low after a single subcutaneousdose of Compound 15/Alhydrogel, or after a single intravenous dose ofAlCl₃·6H₂O.

Finally, the pharmacokinetic parameters obtained for Compound 15 after asingle subcutaneous dose of Suspension H were similar to those obtainedin Example 5, specifically a mean C_(max) of 75.8 ng/mL for Compound 15was obtained, with a mean T_(max) of 5 hours post dose. The AUC_(last)and AUC_(inf) were 3660 ng·h/mL and 3730 ng/mL, respectively. Theelimination half-life was 66.2 hours, further demonstrating controlledrelease of Compound 15 at the injection site.

Example 13: In Vivo Efficacy as Single Agent Suspension I 4 mg/mLCompound 15, 6 mg/mL Aluminum Hydroxide and 0.9% NaCl in 50 mM Tris (pH7.4)—Compound 15/Alhydrogel® (1:1.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 10 mg/mL of Compound 15, 2.25% (w/v)NaCl in 125 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 4 mg/mL Compound 15, 6 mg/mL Aluminumhydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a 1.5:1 ratio ofAlhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% VolumeFinal Conc Final Conc pound 15 stock Alhydrogel ® Water (mg/mL) (mg/mL)15 ratio (mL) (mL) (mL) 4 6 1.5:1 2.0 3.0 0.0

Suspension J 2 mg/mL Compound 15, 3 mg/mL Aluminum Hydroxide and 0.9%NaCl in 50 mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:1.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 5 mg/mL of Compound 15, 2.25% (w/v)NaCl in 125 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 2 mg/mL Compound 15, 3 mg/mL Aluminumhydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a 1.5:1 ratio ofAlhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% VolumeFinal Conc Final Conc pound 15 stock Alhydrogel ® Water (mg/mL) (mg/mL)15 ratio (mL) (mL) (mL) 2 3 1.5:1 2.0 1.5 1.5

Suspension K 1 mg/mL Compound 15, 1.5 mg/mL Aluminum Hydroxide and 0.9%NaCl in 50 mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:1.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 2.5 mg/mL of Compound 15, 2.25% (w/v)NaCl in 125 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 1 mg/mL Compound 15, 1.5 mg/mL Aluminumhydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a 1.5:1 ratio ofAlhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% VolumeFinal Conc Final Conc pound 15 stock Alhydrogel ® Water (mg/mL) (mg/mL)15 ratio (mL) (mL) (mL) 1 1.5 1.5:1 2.0 0.75 2.25

Suspension L 0.5 mg/mL Compound 15, 0.75 mg/mL Aluminum Hydroxide and0.9% NaCl in 50 mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:1.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 1.25 mg/mL of Compound 15, 2.25% (w/v)NaCl in 125 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 0.5 mg/mL Compound 15, 0.75 mg/mL Aluminumhydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a 1.5:1 ratio ofAlhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% VolumeFinal Conc Final Conc pound 15 stock Alhydrogel ® Water (mg/mL) (mg/mL)15 ratio (mL) (mL) (mL) 0.5 0.75 1.5:1 2.0 0.375 2.63

Controls:

-   -   a) No treatment    -   b) Compound 15 only: 2 mg/mL of Compound 15 and 0.9% NaCl in 50        mM Tris (pH 7.4)    -   c) Alhydydrogel® only: 3 mg/mL of Alhydrogel® in 50 mM Tris (pH        7.4) The anti-tumor efficacy of Compound 15 adsorbed to        Alhydrogel® was determined using the mouse syngeneic lymphoma        A20 bilateral tumor model in female BALB/c mice.

A20 cells were grown in sterile conditions in a 37° C. incubator with 5%CO₂ for two weeks. Cells were grown in RPMI 1640 medium with 2 mML-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/Lglucose, 10 mM HEPES, and 1.0 mM sodium pyruvate and supplemented with0.05 mM 2-mercaptoethanol, 10% fetal bovine serum. Cells were passagedevery 2-3 days. For the day of implant cells were lifted (passage 12)and re-suspended in HBSS at a concentration of 5×10⁶ cells/100 μL. Cellswere Radil tested for mycoplasma and murine viruses. For each mouse,5×10⁶ cells were implanted by subcutaneous injection into the right andleft flank using a 28.5 g needle (100 μl injection volume). Tumor sizeswere assessed three times a week once tumors were palpable. Tumor sizeswere determined by using caliper measurements, with tumor volumescalculated using the formula: (Length×Width×Width)/2.

The female Balb/c mice bearing the A20 tumors were randomized into 7groups (n=10 mice per group) 8 days post tumor cell implantation with anaverage tumor volume range of 111.40±23.57 mm³. 50 μL of eitherSuspension I, Suspension J, Supension K, Suspension L, Compound 15 onlycontrol or Alhydrogel® only control were intratumorally administered todifferent groups of animals once a week for two weeks. Table 16 givesthe Compound 15 dose obtained from the 50 μL intratumoral administrationof the controls and suspension.

TABLE 16 Com- pound 15 Dose (μg) Compound 15 100 control Alhydrogel ® 0control Suspension I 25 Suspension J 50 Suspension K 100 Suspension L200

Tumor volumes were measured by digital caliper 3 times a week and bodyweights of all animals were recorded throughout the study. The mice weresacrificed when tumor volumes were over 1500 mm3 or mouse was moribund.

FIG. 8 shows the efficacy and dose response of 0 μg, 25 μg, 50 μg, 100μg and 200 μg of Compound 15 adsorbed to aluminum hydroxide (at fixedratio of 1:1.5, w/w, and 97% bound) in the mouse syngeneic lymphoma A20bilateral tumor model. After two weekly doses, 25 μg, 50 μg, 100 μg and200 μg of Compound 15 adsorbed to aluminum hydroxide showed significanttumor growth inhibition (p<0.05 to 0.001) on day 21 in the treated tumorsite with a dose dependent increase in anti-tumor efficacy withintratumoral delivery (i.t.) being observed. However, no significanttumor growth inhibition (p>0.05) on day 21 in distal tumor site tumorwas seen. In addition, after two weekly doses, Compound 15 adsorbed toAlhydrogel® showed better efficacy than 100 μg of Compound 15 alone, and100 μg of Compound 15 alone had no significant difference in both tumorsites.

Example 14: In Vivo Efficacy-Effect of Binding Efficiency Suspension M 2mg/mL Compound 15, 2 mg/mL Aluminum Hydroxide and 0.9% NaCl in 50 mMTris (pH 7.4)—Compound 15/Alhydrogel® (1:1 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 5 mg/mL of Compound 15, 2.25% (w/v)NaCl in 125 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 2 mg/mL Compound 15, 32 mg/mL Aluminumhydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a 1:1 ratio ofAlhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% VolumeFinal Conc Final Conc pound 15 stock Alhydrogel ® Water (mg/mL) (mg/mL)15 ratio (mL) (mL) (mL) 2 2 1:1 2.0 1.0 2.0

Suspension N 2 mg/mL Compound 15, 1.0 mg/mL Aluminum Hydroxide and 0.9%NaCl in 50 mM Tris (pH 7.4)—Compound 15/Alhydrogel® (1:0.5 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 5 mg/mL of Compound 15, 2.25% (w/v)NaCl in 125 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 2 mg/mL Compound 15, 0.5 mg/mL Aluminumhydroxide and 0.9% NaCl in 50 mM Tris (pH 7.4) at a 0.5:1 ratio ofAlhydrogel® to Compound 15.

Com- Aluminum Volume pound 15 Aluminum to Com- Compound Volume 2% VolumeFinal Conc Final Conc pound 15 stock Alhydrogel ® Water (mg/mL) (mg/mL)15 ratio (mL) (mL) (mL) 2 1.0 0.5:1 2.0 0.50 2.50

Control: Alhydydrogel® only: 3 mg/mL of Alhydrogel® in 50 mM Tris (pH7.4)

The effect of binding efficiency of Compound 15 adsorbed to Alhydrogel®on anti-tumor efficacy was determined using the mouse syngeneic lymphomaA20 bilateral tumor model in female BALB/c mice (described in Example12). A dose response study was performed using Suspension J, SuspensionM and Suspension N having a Compound 15/Alhydrogel® ratio and bindingefficiency of 1:1.5 (approx. 98% bound), 1:1 (approx. 80% bound) and1:0.5 (approx. 50% bound), respectively.

Female Balb/c mice bearing the A20 tumors were randomized into 4 groups(n=10 mice per group) 9 days post tumor cell implantation with anaverage tumor volume range of 128.43±23.42 mm³. 50 μL of eitherSuspension J, Supension M, Suspension N or Alhydrogel® only control wereintratumorally administered to different groups of animals. The 50 μLdose volume intratumoral administration 100 μg of Compound 15. Tumorvolumes were measured and calculated as in Example 12. The mice would besacrificed for tumor volume over 1500 mm3 or the mouse was moribund.

FIG. 9 shows the efficacy and dose response of 100 μg of Compound 15adsorbed to aluminum hydroxide at approx. 98% bound (Compound15/Alhydrogel® ratio of 1:1.5, w/w), at approx. 80% bound (Compound15/Alhydrogel® ratio of 1:1, w/w) and at approx. 50% bound (Compound15/Alhydrogel® ratio of 1:0.5, w/w). After a single dose, Compound 15was found to induce tumor regression only when it was approx. 98% boundto Alhydrogel®, and showed reduced efficacy with decreasing Alhydrogelbinding percentages.

Example 15: in vivo efficacy as agent in combination with one or morecheckpoint inhibitors Suspension O 1 Mg/mL Compound 15, 2 mg/mL AluminumHydroxide and 7.5% (w/v) Sucrose in 16 mM Tris (pH 7.4)—Compound15/Alhydrogel® (1:2 Ratio)

2% Alhydrogel® (aluminum hydroxide gel: 10 mg/mL aluminum) was obtainedfrom Brenntag Biosector A/S, Elsenbakken 23, 3600 Frederikssund, Denmarkand was used as stock for dilution to obtain the required concentrationof aluminum. A stock solution of 1.25 mg/mL of Compound 15, 9.375% (w/v)sucrose in 20 mM Tris (pH 7.4) buffer was prepared for dilution with the2% Alhydrogel® stock. The table below gives the volumes used to make 5mL of a suspension comprising 1 mg/mL Compound 15, 2 mg/mL Aluminumhydroxide and 7.5% (w/v) sucrose in 16 mM Tris (pH 7.4) at a 2:1 ratioof Alhydrogel® to Compound 15.

Com- Aluminum Volume Volume pound 15 Aluminum to Com- Compound 2% FinalConc Final Conc pound 15 stock Alhydrogel ® (mg/mL) (mg/mL) 15 ratio(mL) (mL) 1 2 2:1 4 1

Reagents.

Compound 15 was in a suspension with Alhydrogel® (Suspension N).

Anti-PD-L1 antibody (BAP058-hum13 with heavy chain variable domain ofSEQ ID NO:7 and a light chain variable domain of SEQ ID NO:17).

Anti-CTLA4 was purchased from Bio X Cell. Clone 9D9, Lot No:5311-11/1014. Cat No: BE0146.

Establishment of Mouse Colon Cancer Syngeneic MC38 Tumor Model

MC38 cells were grown in sterile conditions in a 37° C. incubator with5% CO₂ for two weeks. The cells were cultured in Dulbecco's ModifiedEagle's medium (DMEM) media supplemented with 10% FBS, cells were passedevery 2-3 days. On the day of injection, cells were harvested (Passage12) and re-suspended in Hanks' Balanced Salt Solution (HBSS) at aconcentration of 2.5×106/ml. Cells were Radil tested for mycoplasma andmurine viruses.

For each mouse, 0.25×10⁶ cells were implanted with subcutaneouslyinjection into right flank using a 28½ g needle (100 μL injectionvolume). After the first implantation on day 3 (0.25×10⁶) cells areimplanted with a subcutaneous injection into left flank using a 28 ½ gneedle (100 μL injection volume). Tumor sizes were assessed three timesa week once tumors were palpable. Tumor sizes were determined by usingcaliper measurements, with tumor volumes calculated using the formula:(Length×Width×Width)/2.

Dosing and Sampling in MC38 Tumor Bearing C57/BL6 Mice

Female C57BL/6 mice bearing the MC38 tumors were randomized into 7groups (n=9 mice per group) 9 days post tumor cell implantation with anaverage tumor volume range of 69.09-142.25 mm³, and the separate groupsof tumor bearing mice received treatment as shown in Table 17.

TABLE 17 Treat- Dose Route of Group ment Dose Volume AdministrationSchedule 1 No — — — — treatment 2 Com- 50 50 (μL) of Intratumoral once apound 15 (μg) (Suspension N) (i.t.) week for 2 weeks 3 aPD-L1 10 10(μL/g) Intra- twice a (mg/kg) peritoneally week for (i.p.) 2 weeks 4aCTLA4 10 10 (μL/g) Intra- twice a (mg/kg) peritoneally week for (i.p.)2 weeks 5 Com- 50 50 (μL) of Intratumoral once a pound 15 (μg)(Suspension N) (i.t.) week for 2 weeks aPD-L1 10 10 (μL/g) Intra- twicea (mg/kg) peritoneally week for (i.p.) 2 weeks 6 Com- 50 50 (μL) ofIntratumoral once a pound 15 (μg) (Suspension N) (i.t.) week for 2 weeksaCTLA4 10 10 (μL/g) Intra- twice a (mg/kg) peritoneally week for (i.p.)2 weeks 7 Com- 50 50 (μL) of Intratumoral once a pound 15 (μg)(Suspension N) (i.t.) week for 2 weeks aPD-L1 10 10 (μL/g) Intra- twicea (mg/kg) peritoneally week for (i.p.) 2 weeks aCTLA4 10 10 (μL/g)Intra- twice a (mg/kg) peritoneally week for (i.p.) 2 weeks

-   -   where the anti-PD-L1 antibody solution was 10 (mg/mL) in        phosphate buffered saline (PBS) (pH 7) at and the anti-CTLA4        antibody solution was 10 (mg/mL) in phosphate buffered saline        (PBS) (pH 7).

The anti-tumor efficacy of Compound 15 adsorbed to aluminum hydroxide(Alhydrogel®) alone or in combination with checkpoint inhibitors, wasdetermined using a contralateral MC38 colon cancer model. The tumorvolume was obtained after two weekly intratumoral injections of Compound15 adsorbed to aluminum hydroxide (50 μg each) either alone (Group 2),in a double combination with intraperitoneal injection (twice weekly) ofan anti-PD-L1 antibody (10 mg/kg) (Group 5), in a double combinationwith intraperitoneal injection (twice weekly) of an anti-CTLA4 antibody(10 mg/kg) (Group 6), or in a triple combination with intraperitonealinjection (twice weekly) of an anti-PD-L1 antibody (10 mg/kg) and withintraperitoneal injection of an anti-CTLA4 antibody (10 mg/kg) (group7). For comparison, data was obtained after an intraperitoneal injection(twice weekly) of the anti-PD-L1 antibody (10 mg/kg) alone (Group 3) andafter an intraperitoneal injection (twice weekly) of the anti-CTLA4antibody (10 mg/kg) alone (Group 4). The untreated control data was alsoobtained (Group 1). FIG. 10A shows the tumor volume at the primaryintratumor injection site and FIG. 10B shows the tumor volume at thedistant contralateral site.

The anti-tumor efficacy of Compound 15 alone (without aluminum hydroxide(Alhydrogel®)) or in combination with checkpoint inhibitors wasdetermined using a contralateral MC38 colon cancer model. The tumorvolume was obtained after two weekly intratumoral injections of Compound15 alone (without aluminum hydroxide (Alhydrogel®) (50 μg each)) or in atriple combination with intraperitoneal injection (twice weekly) of ananti-PD-L1 antibody (10 mg/kg) and anti-CTLA4 antibody (10 mg/kg). Forcomparison data was obtained after an intraperitoneal injection (twiceweekly) of the combination of anti-PD-L1 antibody (10 mg/kg) and theanti-CTLA4 antibody (10 mg/kg) alone. In addition, the anti-tumorefficacy of Compound 15 adsorbed to aluminum hydroxide (Alhydrogel®)alone or in a triple combination with checkpoint inhibitors wasdetermined using a contralateral MC38 colon cancer model. The tumorvolume was obtained after two weekly intratumoral injections of Compound15 adsorbed to aluminum hydroxide (Alhydrogel®) (50 μg each)) alone orin a triple combination with intraperitoneal injection (twice weekly) ofan anti-PD-L1 antibody (10 mg/kg) and anti-CTLA4 antibody (10 mg/kg).For comparison data was obtained after an intraperitoneal injection(twice weekly) of the combination of anti-PD-L1 antibody (10 mg/kg) andthe anti-CTLA4 antibody (10 mg/kg) alone. The untreated control data wasalso obtained. FIG. 10C shows the tumor volume obtained at the primaryintratumor injection site and FIG. 10D shows the tumor volume obtainedat the distant contralateral site.

Dosing as Single Agents:

At the primary injection site anti-CTLA4 alone and was not significantlydifferent from the no treatment group, (p>0.05) with a % T/C of 99.98%.Similarly, Compound 15 alone (without aluminum hydroxide (Alhydrogel®)did not show a difference from the no treatment group. However,anti-PD-L1 alone was significantly different, (p<0.05) with a % T/C of56.22% and Compound 15/Alhydrogel® alone was also significantlydifferent, (p<0.0001) with a % T/C of 25.22%. Compound 15 adsorbed toaluminum hydroxide appeared to have improved efficacy as a single agentat the site of injection relative to either antibody administered assingle agents.

At the contralateral tumor site anti-CTLA4 alone was not significantlydifferent from the no treatment group, (p>0.05) with a % T/C of 79.72%.Similarly, Compound 15 alone (without aluminum hydroxide (Alhydrogel®)did not show a difference from the no treatment group. However,anti-PD-L1 alone was significantly different, (p<0.001) with a % T/C of27.02%, and Compound 15/Alhydrogel® alone was also significantlydifferent, (p<0.01) with a T/C of 29.50%. Compound 15 adsorbed toaluminum hydroxide appeared to have improved efficacy as a single agentat the distant site relative to either antibody administered as singleagents.

Dosing in Combination with a Checkpoint Inhibitor:

The combination of intratumoral administration of Compound 15 adsorbedto aluminum hydroxide with intraperitoneal injection of anti-PD-L1exhibited significant improvement in anti-tumor efficacy at both theprimary intratumoral injection site and contralateral site, with(p<0.0001) with a T/C of 8.93% and (p<0.0001) with a % T/C of 5.39%, forthe primary intratumoral injection site and contralateral site,respectively, being obtained.

At the primary intratumor injection site the combination of intratumoraladministration of Compound 15 adsorbed to aluminum hydroxide withintraperitoneal administration of anti-CTLA4 exhibited similar behavioras that obtained for Compound 15 adsorbed to aluminum hydroxideadministered alone, while at the contralateral site the combinationappeared less effective than Compound 15 adsorbed to aluminum hydroxideadministered alone. However a significant difference from thenon-treated group was observed, with a (p<0.0001) with a % T/C of 26.74%and a (p<0.05) with a % T/C of 48.70%, for the primary intratumoralinjection site and contralateral site, respectively, being obtained.

In addition, dosing anti-PD-L1 and anti-CTLA-4 in combination did notresult in complete tumor regression (data not shown).

Dosing in Combination with Two Checkpoint Inhibitors:

The triple combination of intratumoral injection of Compound 15 adsorbedto aluminum hydroxide, intraperitoneal injection of the anti-PD-L1antibody and intraperitoneal injection of the anti-CTLA4 antibody showedfull tumor regression in 7 of 9 animals, with a (p<0.0001) with a T/C of−38.51% and a (p<0.0001) with a T/C of −9.60% for the primaryintratumoral injection site and contralateral site, respectively, beingobtained.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

1. A pharmaceutical composition comprising a compound having thestructure of Formula (A), or a pharmaceutically acceptable salt thereof,aluminum-containing particles, a buffering agent and one or morepharmaceutically acceptable excipients:

wherein: R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or—C(═O)CF₂P(O)(OH)₂; R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴,—OL₂R⁴, —OR⁴, —OL₂R⁶, —OL₂L₃R⁶, —OL₂L₃L₂R⁶, —OL₂L₃R₄—OL₂L₃L₂R⁴ or —OCH₃;each R³ is independently selected from H and fluoro; R⁴ is —P(O)(OH)₂,R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH; R⁶ is —CF₂P(O)(OH)₂ or —C(O)OH; L₁ isC₁-C₆alkylene, C₂-C₆alkenylene or —((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, whereinthe C₁-C₆alkylene and C₂-C₆alkenylene of L₁ are substituted with 0 to 4fluoro groups; each L₂ is independently selected from C₁-C₆alkylene and—((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂ issubstituted with 0 to 4 fluoro groups; L₃ is arylene or a 5-6 memberedheteroarylene; each p is independently selected from 1, 2, 3, 4, 5 and6, and q is 1, 2, 3 or
 4. 2. The pharmaceutical composition of claim 1wherein the composition comprises a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, a bufferingagent, a pharmaceutically acceptable excipient selected from mannitoland sucrose, wherein the composition has a pH in the range of 6.5 to9.0, and the aluminum-containing particles are a suspension ofaluminum-containing particles.
 3. The pharmaceutical composition ofclaim 1 or claim 2, wherein the aluminum-containing particles arealuminum hydroxide particles, aluminum oxyhydroxide particles oraluminum hydroxyphosphate particles and the suspension ofaluminum-containing particles is a suspension of aluminum hydroxideparticles, aluminum oxyhydroxide particles or aluminum hydroxyphosphateparticles.
 4. The pharmaceutical composition of any one of claims 1 to3, wherein the aluminum-containing particles are aluminum hydroxideparticles, and the suspension of aluminum-containing particles is asuspension of aluminum hydroxide particles.
 5. The pharmaceuticalcomposition of any one of claims 1 to 4, wherein the compositioncomprises a compound having the structure of Formula (A), or apharmaceutically acceptable salt thereof, a suspension of aluminumhydroxide particles, Tris buffer and mannitol.
 6. The pharmaceuticalcomposition of any one of claims 1 to 5, wherein the compositioncomprises 0.5 to 2 mg/mL of a compound having the structure of Formula(A), or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.
 7. Thepharmaceutical composition of any one of claims 1 to 6, wherein thecomposition comprises 1 mg/mL of a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, and wherein thecomposition has a pH in the range of 7.0 to 8.0.
 8. The pharmaceuticalcomposition of any one of claims 1 to 7, wherein the compositioncomprises 1 mg/mL of a compound having the structure of Formula (A), ora pharmaceutically acceptable salt thereof, 16 mM Tris buffer, 7.5%(w/v) mannitol, and a suspension of aluminum hydroxide particles havingan aluminum content of 2 mg/mL, and wherein the composition has a pH inthe range of 7.0 to 8.0.
 9. The pharmaceutical composition of any one ofclaims 1 to 7, wherein the composition comprises 1 mg/mL of a compoundhaving the structure of Formula (A), or a pharmaceutically acceptablesalt thereof, 5 mM Tris buffer, 8.25% (w/v) mannitol, and a suspensionof aluminum hydroxide particles having an aluminum content of 2 mg/mL,and wherein the composition has a pH in the range of 7.0 to 8.0.
 10. Thepharmaceutical composition of any one of claims 1 to 7, wherein thecomposition comprises 1 mg/mL of a compound having the structure ofFormula (A), or a pharmaceutically acceptable salt thereof, 5 mM Trisbuffer, 5.5% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, and wherein thecomposition has a pH in the range of 7.0 to 8.0.
 11. The pharmaceuticalcomposition of any one of claims 1 to 10, wherein the (w/w) ratio of theweight of compound of Formula A to the weight of aluminum in thesuspension of aluminum-containing particles is in the range from 1:1 to1:20.
 12. The pharmaceutical composition of any one of claims 1 to 11,wherein the (w/w) ratio of the weight of compound of Formula A to theweight of aluminum in the suspension of aluminum-containing particles is1:2.
 13. The pharmaceutical composition of any one of claims 1 to 12,wherein the compound having the structure of Formula (A) is:3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid;3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid;3-(5-amino-2-(4-(4,4-difluoro-4-phosphonobutoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid;3-(5-amino-2-(2-methyl-4-(3-phosphonopropoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid;3-(5-amino-2-(4-(2-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid;3-(5-amino-2-(2-methyl-4-(2-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid;3-(5-amino-2-(2-methyl-4-(2-(2-phosphonoethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.(3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propyl)phosphonicacid;4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyldihydrogen phosphate;((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phosphonicacid;5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluoropentylphosphonicacid;(4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorobutyl)phosphonicacid;(3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)-1,1-difluoropropyl)phosphonicacid;3-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)-1,1-difluoropropylphosphonicacid;2-(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)-1,1-difluoroethylphosphonicacid;(3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenyl)phosphonicacid;(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethyl)phosphonicacid;(6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexyl)phosphonicacid;(6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)-1,1-difluorohexyl)phosphonicacid;(4-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)benzyl)phosphonicacid;(2-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)ethyl)phosphonicacid;(5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)pentyl)phosphonicacid, and(4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)butyl)phosphonicacid.2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonicacid;(E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinyl)phosphonicacid;2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonicacid;(E)-(2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinyl)phosphonicacid, or(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonyl)phosphonicacid.
 14. The pharmaceutical composition of any one of claims 1 to 13,wherein the compound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.
 15. The pharmaceutical composition of any one of claims 1 to 13,wherein the compound is3-(5-amino-2-(2-methyl-4-(2-(2-(2-phosphonoethoxy)ethoxy)ethoxy)phenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.
 16. The pharmaceutical composition of any one of claims 1 to 5,wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, a suspension ofaluminum hydroxide particles, Tris buffer and mannitol.
 17. Thepharmaceutical composition of any one of claims 1 to 5 or 16, whereinthe composition comprises 0.5 to 2 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 1 to 4 mg/mL.
 18. Thepharmaceutical composition of any one of claims 1 to 5 or 16 to 17,wherein the composition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-20 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles having an aluminum content of 2 mg/mL, and wherein thecomposition has a pH in the range of 7.0 to 8.0.
 19. The pharmaceuticalcomposition of any one of claims 1 to 5 or 16 to 18, wherein thecomposition comprises 1 mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 16 mM Tris buffer,7.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.
 20. The pharmaceutical composition of anyone of claims 1 to 5 or 16 to 18, wherein the composition comprises 1mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,8.25% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.
 21. The pharmaceutical composition of anyone of claims 1 to 5 or 16 to 18, wherein the composition comprises 1mg/mL of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5 mM Tris buffer,5.5% (w/v) mannitol, and a suspension of aluminum hydroxide particleshaving an aluminum content of 2 mg/mL, and wherein the composition has apH in the range of 7.0 to 8.0.
 22. The pharmaceutical composition of anyone of claims 1 to 5 or 16 to 21, wherein the (w/w) ratio of the weightof3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, to the weight ofaluminum in the suspension of aluminum-containing particles is in therange from 1:1 to 1:20.
 23. The pharmaceutical composition of any one ofclaims 1 to 5 or 16 to 21, wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, to the weight ofaluminum in the suspension of aluminum-containing particles is 1:2. 24.The pharmaceutical composition of any one of claims 1 to 5 or 16 to 21,wherein the composition comprises3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid, or a pharmaceutically acceptable salt thereof, 5-100 mM Trisbuffer, 5-10% (w/v) mannitol, and a suspension of aluminum hydroxideparticles, and wherein the (w/w) ratio of the weight of3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid to the weight of aluminum in the suspension of particles is 1:20.25. The pharmaceutical composition of any one of claims 1 to 24 furthercomprising an additional therapeutic agent.
 26. The pharmaceuticalcomposition of claim 25, wherein the additional therapeutic agents is acheckpoint inhibitor, a TLR9 agonist, a TLR8 agonist, a TLR7 agonist, aSTING agonist or a chemotherapeutic agent.
 27. A pharmaceuticalcombination comprising: a) a first pharmaceutical composition of any oneof claims 1 to 24, and b) a second pharmaceutical composition comprisinga checkpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptorinhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1inhibitor or a PD-L2 inhibitor.
 28. A pharmaceutical combinationcomprising: a) a first pharmaceutical composition of any one of claims 1to 24, and b) a second pharmaceutical composition comprising a PD-1receptor inhibitor.
 29. A pharmaceutical combination comprising: a) afirst pharmaceutical composition of any one of claims 1 to 24, and b) asecond pharmaceutical composition comprising a PD-L1 inhibitor.
 30. Apharmaceutical combination comprising: a) a first pharmaceuticalcomposition of any one of claims 1 to 24, and b) a second pharmaceuticalcomposition comprising an anti-PD-L1 antibody.
 31. A pharmaceuticalcombination comprising: a) a first pharmaceutical composition of any oneof claims 1 to 24, and b) a second pharmaceutical composition comprisingan anti-PD-1 antibody.
 32. A pharmaceutical combination comprising: a) afirst pharmaceutical composition of any one of claims 1 to 24, b) asecond pharmaceutical composition comprising a checkpoint inhibitorselected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, aLAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptorinhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2inhibitor, and c) a third pharmaceutical composition comprising acheckpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptorinhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1inhibitor or a PD-L2 inhibitor, wherein the checkpoint of the thirdcomposition is different than the checkpoint inhibitor in the secondcomposition.
 33. A pharmaceutical combination comprising: a) a firstpharmaceutical composition of any one of claims 1 to 24, b) a secondpharmaceutical composition comprising a PD-L1 inhibitor, and c) a thirdpharmaceutical composition comprising a CTLA-4 receptor inhibitor.
 34. Apharmaceutical combination comprising: a) a first pharmaceuticalcomposition of any one of claims 1 to 24, b) a second pharmaceuticalcomposition comprising a PD-1 inhibitor, and c) a third pharmaceuticalcomposition comprising a CTLA-4 receptor inhibitor.
 35. A pharmaceuticalcombination comprising: a) a first pharmaceutical composition of any oneof claims 1 to 24, b) a second pharmaceutical composition comprising ananti-PD-L1 antibody, and c) a third pharmaceutical compositioncomprising an anti-CTLA-4 antibody.
 36. A pharmaceutical combinationcomprising: a) a first pharmaceutical composition of any one of claims 1to 24, b) a second pharmaceutical composition comprising an anti-PD-1antibody, and c) a third pharmaceutical composition comprising ananti-CTLA-4 antibody.
 37. A method for treating a solid tumor byadministering to a subject in need thereof a pharmaceutical compositionof any one of claims 1 to 26, or a pharmaceutical combination of any oneof claims 27 to
 36. 38. A method for treating a solid tumor byadministering to a subject in need thereof a pharmaceutical combinationcomprising: a) a first pharmaceutical composition of any one of claims 1to 24, b) a second pharmaceutical composition comprising a checkpointinhibitor selected from a CTLA-4 receptor inhibitor, a PD-1 receptorinhibitor, a LAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLAreceptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or aPD-L2 inhibitor, and c) a third pharmaceutical composition comprising acheckpoint inhibitor selected from a CTLA-4 receptor inhibitor, a PD-1receptor inhibitor, a LAG-3 receptor inhibitor, TIM-3 receptorinhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1inhibitor or a PD-L2 inhibitor, wherein the checkpoint of the thirdcomposition is different than the checkpoint inhibitor in the secondcomposition, and wherein the first pharmaceutical composition isadministered intratumorally, and the second pharmaceutical compositionand the third pharmaceutical composition are administeredintratumorally, intramuscularly, intradermally, subcutaneously,intravenously, by intraperitoneal injection, by lavage or by infusion.39. A method for treating a solid tumor by administering to a subject inneed thereof a pharmaceutical combination comprising: a) a firstpharmaceutical composition of any one of claims 1 to 24, and a b) asecond pharmaceutical composition comprising a checkpoint inhibitorselected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, aLAG-3 receptor inhibitor, TIM-3 receptor inhibitor, a BTLA receptorinhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor or a PD-L2inhibitor, wherein the first pharmaceutical composition is administeredintratumorally, and the second pharmaceutical composition isadministered intratumorally, intramuscularly, intradermally,subcutaneously, intravenously, by intraperitoneal injection, by lavageor by infusion.
 40. The method of any one of claims 37 to 39, whereinthe solid tumor is head and neck squamous cell carcinoma (HNSCC),melanoma or a visceral tumor.
 41. Use of a pharmaceutical composition ofany one of claims 1 to 26, or use a pharmaceutical combination of anyone of claims 27 to 36, in treating a solid tumor.
 42. The use of claim41, wherein the solid tumor is head and neck squamous cell carcinoma(HNSCC), melanoma or a visceral tumor.
 43. A pharmaceutical compositionof any one of claims 1 to 26, or a pharmaceutical combination of any oneof claims 27 to 36, for use in treating a solid tumor.
 44. Thepharmaceutical composition of claim 43, wherein the solid tumor is headand neck squamous cell carcinoma (HNSCC), melanoma or a visceral tumor.45. A lyophilisate comprising a compound having the structure of Formula(A), or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients:

wherein: R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or—C(═O)CF₂P(O)(OH)₂; R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴,—OL₂R⁴, —OR⁴, —OL₂R⁶, —OL₂L₃R⁶, —OL₂L₃L₂R⁶, —OL₂L₃R₄—OL₂L₃L₂R⁴ or —OCH₃;each R³ is independently selected from H and fluoro; R⁴ is —P(O)(OH)₂,R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH; R⁶ is —CF₂P(O)(OH)₂ or —C(O)OH; L₁ isC₁-C₆alkylene, C₂-C₆alkenylene or —((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, whereinthe C₁-C₆alkylene and C₂-C₆alkenylene of L₁ are substituted with 0 to 4fluoro groups; each L₂ is independently selected from C₁-C₆alkylene and—((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂ issubstituted with 0 to 4 fluoro groups; L₃ is arylene or a 5-6 memberedheteroarylene; each p is independently selected from 1, 2, 3, 4, 5 and6, and q is 1, 2, 3 or
 4. 46. The lyophilisate of claim 45, wherein thecompound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.
 47. A lyophilisate prepared from a solution having a pH between6.5 and 9.0 and comprising a a compound having the structure of Formula(A), or a pharmaceutically acceptable salt thereof, and a bufferingagent:

wherein: R¹ is -L₁R⁴, -L₁R⁵, —OL₁R⁴, —OL₁R⁵, CH₃, —C(═O)P(O)(OH)₂ or—C(═O)CF₂P(O)(OH)₂; R² is -L₂R⁴, -L₂R⁶, -L₂L₃L₂R⁶, -L₂L₃R⁴, -L₂L₃L₂R⁴,—OL₂R⁴, —OR⁴, —OL₂R⁶, —OL₂L₃R⁶, —OL₂L₃L₂R⁶, —OL₂L₃R⁴ —OL₂L₃L₂R⁴ or—OCH₃; each R³ is independently selected from H and fluoro; R⁴ is—P(O)(OH)₂, R⁵ is —CF₂P(O)(OH)₂ or —C(O)OH; R⁶ is —CF₂P(O)(OH)₂ or—C(O)OH; L₁ is C₁-C₆alkylene, C₂-C₆alkenylene or—((CR⁴R⁴)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene andC₂-C₆alkenylene of L₁ are substituted with 0 to 4 fluoro groups; each L₂is independently selected from C₁-C₆alkylene and—((CR³R³)_(p)O)_(q)(CH₂)_(p)—, wherein the C₁-C₆alkylene of L₂ issubstituted with 0 to 4 fluoro groups; L₃ is arylene or a 5-6 memberedheteroarylene; each p is independently selected from 1, 2, 3, 4, 5 and6, and q is 1, 2, 3 or
 4. 48. The lyophilisate of claim 47, wherein thecompound is3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoicacid.
 49. A pharmaceutical composition prepared by reconstituting alyophilisate of any one of claims 45 to 48 with water and admixing witha suspension of aluminum-containing particles.
 50. The pharmaceuticalcomposition of claim 49 prepared by reconstituting a lyophilisate of anyone of claims 45 to 48 with water and admixing with a suspension ofaluminum-containing particles having an aluminum content of 1 to 4mg/mL.
 51. The pharmaceutical composition of claim 49 or 50, wherein thealuminum-containing particles are aluminum hydroxide particles.